Maternal Outcomes Among Pregnant Women With Congenital Heart Disease-Associated Pulmonary Hypertension.

BACKGROUND: Studies focused on pregnant women with congenital heart disease (CHD)-associated pulmonary hypertension (PH) are scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women with CHD with and without PH. METHODS: Outcomes for pregnant women with CHD were evaluated retrospectively from 1993 to 2016 and prospectively from 2017 to 2019 from 7 tertiary hospitals. PH was diagnosed on the basis of echocardiogram or catheterization. The incidence of maternal death, cardiac complications, and obstetric and offspring complications was compared for women with CHD and no PH, mild, and moderate-to-severe PH. RESULTS: A total of 2220 pregnant women with CHD had completed pregnancies. PH associated with CHD was identified in 729 women, including 398 with mild PH (right ventricle to right atrium gradient 30-50 mm Hg) and 331 with moderate-to-severe PH (right ventricle to right atrium gradient >50 mm Hg). Maternal mortality occurred in 1 (0.1%), 0, and 19 (5.7%) women with CHD and no, mild, or moderate-to-severe PH, respectively. Of the 729 patients with PH, 619 (85%) had CHD-associated pulmonary arterial hypertension, and 110 (15%) had other forms of PH. Overall, patients with mild PH had better maternal outcomes than those with moderate-to-severe PH, including the incidence of maternal mortality or heart failure (7.8% versus 39.6%; P<0.001), other cardiac complications (9.0% versus 32.3%; P<0.001), and obstetric complications (5.3% versus 15.7%; P<0.001). Brain natriuretic peptide >100 ng/L (odds ratio, 1.9 [95% CI, 1.0-3.4], P=0.04) and New York Heart Association class III to IV (odds ratio, 2.9 [95% CI, 1.6-5.3], P<0.001) were independently associated with adverse maternal cardiac events in pregnancy with PH, whereas follow-up with a multidisciplinary team (odds ratio, 0.4 [95% CI, 0.2-0.6], P<0.001) and strict antenatal supervision (odds ratio, 0.5 [95% CI, 0.3-0.7], P=0.001) were protective. CONCLUSIONS: Women with CHD-associated mild PH appear to have better outcomes compared with women with CHD-associated moderate-to-severe PH, and with event rates similar for most outcomes with women with CHD and no PH. Multimodality risk assessment, including PH severity, brain natriuretic peptide level, and New York Heart Association class, may be useful in risk stratification in pregnancy with PH. Follow-up with a multidisciplinary team and strict antenatal supervision during pregnancy may also help to mitigate the risk of adverse maternal cardiac events.

Metabolic biomarkers significantly enhance the prediction of HBV-related ACLF occurrence and outcomes.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality in patients with chronic liver disease. Chronic hepatitis B is the main cause of ACLF (HBV-ACLF) in China and other Asian countries. To improve disease management and survival for patients with ACLF, we aimed to discover novel biomarkers to enhance HBV-ACLF diagnosis and prognostication. METHODS: We performed a metabolomics profiling of 1,024 plasma samples collected from patients with HBV-related chronic liver disease with acute exacerbation at hospital admission in a multi-year and multi-center prospective study (367 ACLF and 657 non-ACLF). The samples were randomly separated into equal halves as a discovery set and a validation set. We identified metabolites associated with 90-day mortality in the ACLF group and the progression to ACLF within 28 days in the non-ACLF group (pre-ACLF) using statistical analysis and machine learning. We developed diagnostic algorithms in the discovery set and used these to assess the findings in the validation set. RESULTS: ACLF significantly altered the plasma metabolome, particularly in membrane lipid metabolism, steroid hormones, oxidative stress pathways, and energy metabolism. Numerous metabolites were significantly associated with 90-day mortality in the ACLF group and/or pre-ACLF in the non-ACLF group. We developed algorithms for the prediction of 90-day mortality in patients with ACLF (area under the curve 0.87 and 0.83 for the discovery set and validation set, respectively) and the diagnosis of pre-ACLF (area under the curve 0.94 and 0.88 for the discovery set and validation set, respectively). To translate our discoveries into practical clinical tests, we developed targeted assays using liquid chromatography-mass spectrometry. CONCLUSIONS: Based on novel metabolite biomarkers, we established tests for HBV-related ACLF with higher accuracy than existing methods. CLINICAL TRIAL NUMBER: NCT02457637 and NCT03641872. IMPACT AND IMPLICATIONS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality affecting 25% of patients hospitalized with cirrhosis. Chronic hepatitis B is the main etiology of ACLF in China and other Asian counties. There is currently no effective therapy. Early diagnosis and accurate prognostication are critical for improving clinical outcomes in patients with ACLF. Based on novel metabolite biomarkers, we developed liquid chromatography-mass spectrometry tests with improved accuracy for the early diagnosis and prognostication of HBV-related ACLF. The liquid chromatography-mass spectrometry tests can be implemented in clinical labs and used by physicians to triage patients with HBV-related ACLF to ensure optimized clinical management.

Multi-omics profiling of papillary thyroid microcarcinoma reveals different somatic mutations and a unique transcriptomic signature.

BACKGROUND: Papillary thyroid microcarcinoma (PTMC) incidence has significantly increased, and some cases still exhibit invasive traits. The entire molecular landscape of PTMC, which can offer hints for the etiology of cancer, is currently absent. METHODS: We compared our findings with those for PTMC in the TCGA by analyzing the largest study at the current stage of whole exome sequencing and RNA-sequencing data from 64 patients with PTMC. Then, we systematically demonstrated the differences between the two PTMC subtypes based on multi-omics analyses. Additionally, we created a molecular prediction model for the PTMC subtypes and validated them among TCGA patients for individualized integrative assessment. RESULTS: In addition to the presence of BRAF mutations and RET fusions in the TCGA cohort, we also discovered a new molecular signature named PTMC-inflammatory that implies a potential response to immune intervention, which is enriched with AFP mutations, IGH@-ext fusions, elevated immune-related genes, positive peroxidase antibody, and positive thyroglobulin antibody. Additionally, a molecular prediction model for the PTMC-inflammatory patients was created and validated among TCGA patients, while the prognosis for these patients is poor. CONCLUSIONS: Our findings comprehensively define the clinical and molecular features of PTMC and may inspire new therapeutic hypotheses.

Association between use of antihypertensive drugs and the risk of cancer: a population-based cohort study in Shanghai.

BACKGROUND: Previously studies shown a potential risk of antihypertensive medicines in relation to cancer susceptibility, which creating significant debate in the scientific community and public concern. We sought to investigate the relationship between antihypertensive medicines and cancer risk, by drug type and class. METHODS: We conducted a population-based cohort study and enrolled patients diagnosed with hypertension from community healthcare centers in Changning District, Shanghai, China. Antihypertensive drug administration were classified as five common antihypertensive drugs. The main outcomes were incidence of total cancer and by major cancer type. RESULTS: Between January 2013 and December 2017, a total of 101,370 hypertensive patients were enrolled in this cohort. During a mean follow-up of 5.1 (SD 1.3) years, 4970 cancer cases were newly diagnosed in the cohort. CCBs were the most frequently used antihypertensives which were associated with a moderately increased risk of total cancer (hazard ratio, HR = 1.11, 95% CI: 1.05-1.18). The second commonly used drug ARBs were also associated with increased risk of total cancer (HR = 1.10, 95%CI: 1.03-1.17) as well as lung and thyroid cancers (HR = 1.21, 95%CI: 1.05-1.39; HR = 1.62 95%CI: 1.18-2.21, respectively). No significant association was found between cancer and other antihypertensives. Hypertensive patients who use more than one class of antihypertensives drugs had a higher risk of total cancer (HR: 1.22, 95%CI: 1.10-1.35 for two classes; HR: 1.22, 95%CI: 1.03-1.45 for three or more classes), and a possible dose-response relationship was suggested (P for trend < 0.001). The risk of thyroid cancer was higher in hypertensive patients prescribed with three or more antihypertensive classes. CONCLUSIONS: Use of ARBs or CCBs may be associated with an increased risk of total cancer. Taking more than one class of antihypertensives drugs appeared to have a higher risk for total cancer.

Severe anemia is associated with increased short-term and long-term mortality in patients hospitalized with cirrhosis.

INTRODUCTION AND OBJECTIVES: The relationship between anemia and the outcome of patients with cirrhosis is not completely clear. Therefore, we performed this large-scale epidemiological study to investigate the prevalence and severity of anemia in patients with cirrhosis and acute decompensation or liver injury and how anemia impacts short-term and long-term outcomes. PATIENTS AND METHODS: Patients with cirrhosis and acute decompensation (AD) or acute liver injury (ALI) were enrolled in the Chinese AcuTe on CHronic LIver FailurE (CATCH-LIFE) studies, which consisted of two large, multicenter, prospective, observational cohorts between January 2015 and December 2016 and July 2018 and January 2019. We conducted data analysis on the prevalence of anemia and determined the relationship between anemia and prognosis. RESULTS: Among 1979 patients, 1389 (70.2%) had anemia, among whom 599 (41.3%) had mild anemia, 595 (15.8%) had moderate anemia and 195 (2.4%) had severe anemia. A linear association between hemoglobin level and 90-day or 1-year LT-free mortality was shown, and a 10 g/L decrease in hemoglobin level was associated with a 6.8% extra risk of 90-day death and a 5.7% extra risk of 1-year death. Severe anemia was an independent risk factor for 90-day [HR=1.649 (1.100, 2.473), p=0.016] and 1-year LT-free mortality [HR=1.610 (1.159, 2.238), p=0.005]. Multinomial logistic regression analysis further identified that severe anemia was significantly associated with post-28-day mortality but not within-28-day mortality. CONCLUSIONS: Anemia is common in patients with cirrhosis admitted for acute events. Severe anemia was associated with poor 90-day and 1-year prognoses in these patients.

Abnormal subchondral trabecular bone remodeling in knee osteoarthritis under the influence of knee alignment.

OBJECTIVE: This study aimed to investigate the abnormal subchondral trabecular bone (STB) remodeling in knee osteoarthritis (OA) under the influence of knee alignment [hip-knee-ankle (HKA) angle]. DESIGN: Forty-one patients with knee OA underwent radiographic examination before total knee arthroplasty (TKA) for the measurement of HKA angle. Tibial plateau specimens obtained during TKA were used for histomorphometric analyses to assess STB remodeling and cartilage degradation. Tartrate-resistant acidic phosphatase (TRAP) staining was used to test osteoclast activity. Osterix, osteocalcin, and sclerostin expression in the STB were determined using immunohistochemistry. RESULTS: The interaction between HKA angle and side (medial vs lateral of tibial plateau) was the main significant influence factor for STB remodeling and microstructure. The STB with the deviation of the knee alignment was accompanied by obvious abnormal bone remodeling and microstructural sclerosis. Bone volume fraction (BV/TV) was the only significant influence factor for OARSI score, the larger the BV/TV of STB, the higher the OARSI score of cartilage. Moreover, the tibial plateau affected by alignment had more TRAP + osteoclasts, Osterix + osteoprogenitors, and osteocalcin + osteoblasts and fewer sclerostin + osteocytes. CONCLUSIONS: The variation of tibial plateau STB remodeling activity and microstructure was associated with HKA angle and cartilage degradation. Knee malalignment may cause abnormal STB remodeling and microstructural sclerosis, which may potentially affect load stress transmission from the cartilage to the STB, thus resulting in accelerated knee OA progression.

Evaluation of whole axillary status with lymphatic contrast-enhanced ultrasound in patients with breast cancer.

OBJECTIVES: This study aims to evaluate the whole axillary status of patients with breast cancer by lymphatic contrast-enhanced ultrasound (LCEUS). METHODS: LCEUS was applied for 169 patients with suspected breast cancer. Abnormal patterns in lymphatic channels, sentinel lymph nodes (SLNs), and non-enhanced but abnormal lymph nodes were investigated. The signs of distorted, attenuated, netted, or interrupted lymphatic channels, defective-filling or no-filling SLNs, and the appearance of non-enhanced but abnormal lymph nodes were designated as features of axillary metastasis. A positive outcome was given when any of the abnormal patterns was found in the LCEUS. The diagnostic efficiencies were calculated to differentiate the axillary lymphatic status using LCEUS for the whole axilla, compared with conventional ultrasound (US) and LCEUS for SLNs. RESULTS: The LCEUS procedure was successfully performed for 157 breast cancer patients with axillary dissection. Compared to normal axillae, abnormal patterns had a significantly higher frequency in metastatic axillae (p = 0.000). Using conventional US to evaluate the whole axillae, the diagnostic sensitivity, specificity, and accuracy were 69.1%, 71.9%, and 70.7%, respectively. When LCEUS was used for SLN evaluation to predict the whole axilla, the diagnostic sensitivity, specificity, and accuracy were 66.2%, 89.9%, and 79.6%, respectively. When LCEUS was used as the whole axillary evaluation method, the diagnostic sensitivity, specificity, and accuracy were 76.5%, 86.5%, and 82.2%, respectively. CONCLUSION: LCEUS can be an accurate method to observe the whole axillae in breast cancer patients. Lymphatic channels, SLNs, and non-enhanced but abnormal lymph nodes constitute the LCEUS for whole axillary evaluation. KEY POINTS: • LCEUS can be an accurate method to observe the whole axillae in breast cancer patients. • Three aspects in the LCEUS for whole axillary evaluation are the lymphatic channels, sentinel lymph nodes (SLNs), and non-enhanced but abnormal lymph nodes. • Signs of distorted, attenuated, netted, or interrupted lymphatic channels, defective-filling or no-filling SLNs, and the appearance of non-enhanced but abnormal lymph nodes were considered as features of axillary metastasis.

Increasing Gap Between Thyroid Cancer Incidence and Mortality in Urban Shanghai, China: An Analysis Spanning 43 Years.

OBJECTIVE: To examine the secular trends of thyroid cancer incidence and mortality and to estimate the proportion of thyroid cancer cases potentially attributable to overdiagnosis. METHODS: Data on thyroid cancer cases from 1973 to 2015 were obtained from the Shanghai Cancer Registry. The average annual percent change (AAPC) was evaluated using the joinpoint regression analysis. The age, period, and birth cohort effects were assessed using an age-period-cohort model. The overdiagnosis of thyroid cancer cases was estimated based on the difference between observed and expected incidences using the rates of Nordic countries as reference. RESULTS: From 1973 to 2015, the number of thyroid cancer cases was 23 117, and 75% of the patients were women. The age-standardized rates were seven- to eightfold higher from 2013 to 2015 than from 1973 to 1977. Compared with relatively stable mortality, thyroid cancer incidence was dramatically increased from 2002 to 2015 in both sexes, with significant trends (men: AAPC = 21.84%, 95% CI: 18.77%-24.98%, P < .001; women: AAPC = 18.55%, 95% CI: 16.49%-20.64%, P < .001). The proportion of overdiagnosis has gradually increased over time, rising from 68% between 2003 and 2007 to more than 90% between 2013 and 2015. This increasing trend appeared to be similar between men and women. CONCLUSION: An increasing gap between thyroid cancer incidence and mortality was observed in Shanghai, and overdiagnosis has contributed substantially to the rise of incidence, which calls for an urgent update on the practice of thyroid examination.

Association between nighttime-daytime sleep patterns and chronic diseases in Chinese elderly population: a community-based cross-sectional study.

BACKGROUND: This study aimed to assess the relationship between specific nighttime-daytime sleep patterns and prevalence of different chronic diseases in an elderly population. METHODS: We conducted a community-based cross-sectional study in 4150 elderly Chinese, with an average age of 74 years. Sleep-related variables (nighttime sleep duration, daytime napping and duration) and chronic disease status, including diabetes, cardiovascular diseases (CVD), dyslipidemia cancer and arthritis were collected for the study. Multivariable logistic regression models were used to analyze the relationship between nighttime-daytime sleep patterns and prevalence of chronic diseases. RESULTS: Overall prevalence of any of chronic diseases was 83.8%. Nighttime-daytime sleep patterns were defined according to nighttime sleep duration and habitual nappers/non-nappers. Taking the nighttime-daytime sleep pattern "short nighttime sleep with daytime napping" as reference, those with "long nighttime sleep without daytime napping" had higher prevalence of diabetes [OR and 95% CI, 1.35 (1.01-1.80)] and lower prevalence of arthritis [OR and 95% CI, 0.46 (0.33-0.63)]. And those with "long nighttime sleep with daytime napping" had higher prevalence of diabetes [OR and 95% CI, 1.36 (1.05-1.78)] while lower prevalence of cancer [OR and 95% CI, 0.48 (0.26-0.85)] and arthritis [OR and 95% CI, 0.67 (0.51-0.86)]. Further, in habitual nappers, subjects were classified according to duration of nighttime sleep and daytime naps. Compared to "short nighttime sleep with long daytime napping", individuals with "long nighttime sleep with short daytime napping" had significantly positive association with diabetes prevalence [OR and 95% CI, 1.73 (1.15-2.68)] while border-significantly and significantly negative association with cancer [OR and 95% CI, 0.49 (0.23-1.07)] and arthritis [OR and 95% CI, 0.64 (0.44-0.94)], respectively. CONCLUSIONS: Elderly individuals with chronic diseases had different nighttime-daytime sleep patterns, and understanding these relationships may help to guide the management of chronic diseases.

LncRNA LCPAT1 Mediates Smoking/ Particulate Matter 2.5-Induced Cell Autophagy and Epithelial-Mesenchymal Transition in Lung Cancer Cells via RCC2.

BACKGROUND/AIMS: Ecological studies have shown that air pollution and prevalence of cigarette smoking are positively correlated. Evidence also suggests a synergistic effect of cigarette smoking and PM2.5 exposure (Environmental Particulate Matter ≤ 2.5 µm in diameter) on lung cancer risk. We aimed to evaluate the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality and determine its underlying mechanisms in vitro. METHODS: "MOVER" method was used to analyze the interaction between smoking prevalence and PM2.5 pollution in relation to lung cancer mortality. Cell autophagy and malignant behaviors induced by cigarette smoke extract (CSE) and PM2.5 exposure were examined in vitro. Gene expression was examined by qRT-PCR and western blot. RNA and protein interaction was determined using a RNA binding protein immunoprecipitation assay. RESULTS: An increased risk for lung cancer death (RERI (the relative excess risk) =0.28) was observed with a synergistic interaction between cigarette smoking and PM2.5 pollution. Cell migration, invasion, EMT (epithelial-mesenchymal transition) and autophagy were elevated when lung cancer cells were treated with CSE and PM2.5 in combination. A lncRNA, named lung cancer progression-association transcript 1 (LCPAT1), was up-regulated after the treatment of CSE and PM2.5, and knocking down the lncRNA impaired the effect of CSE and PM2.5 on lung cancer cells. In addition, LCPAT1 was shown to bind to RCC2, and RCC2 mediated the effect of LCPAT1 on cell autophagy, migration, invasion and EMT in lung cancer. CONCLUSIONS: Our results suggest that combined exposure to CSE and PM2.5 induces LCPAT1 expression, which up-regulates autophagy, and promotes lung cancer progression via RCC2.

Enhancing the fairness of AI prediction models by Quasi-Pareto improvement among heterogeneous thyroid nodule population.

Artificial Intelligence (AI) models for medical diagnosis often face challenges of generalizability and fairness. We highlighted the algorithmic unfairness in a large thyroid ultrasound dataset with significant diagnostic performance disparities across subgroups linked causally to sample size imbalances. To address this, we introduced the Quasi-Pareto Improvement (QPI) approach and a deep learning implementation (QP-Net) combining multi-task learning and domain adaptation to improve model performance among disadvantaged subgroups without compromising overall population performance. On the thyroid ultrasound dataset, our method significantly mitigated the area under curve (AUC) disparity for three less-prevalent subgroups by 0.213, 0.112, and 0.173 while maintaining the AUC for dominant subgroups; we also further confirmed the generalizability of our approach on two public datasets: the ISIC2019 skin disease dataset and the CheXpert chest radiograph dataset. Here we show the QPI approach to be widely applicable in promoting AI for equitable healthcare outcomes.

Predicting axillary metastasis in breast cancer using lymphatic contrast-enhanced ultrasound-guided fine-needle aspiration of one lymph node.

OBJECTIVES: Fine-needle aspiration (FNA) is a microinvasive method to diagnose lymph nodes. This study aims to determine the capability of lymphatic contrast-enhanced ultrasound (LCEUS)-guided FNA in predicting the axillary metastasis with the target of one lymph node (LN) in patients with breast cancer. METHODS: LCEUS was prospectively performed in 105 patients with breast cancer. The most suspicious LN was targeted based on the characters of LCEUS. FNA was performed in the LN, followed by localization using a guide wire. The detection of lymph cells and/or tumour cells was recognized as a puncture success. Cytologic diagnosis was compared with histologic diagnosis of wire-marked LN for diagnosing accuracy and compared with histologic diagnosis of axillary LNs for predicting accuracy. RESULTS: LCEUS-guided FNA was performed in all 105 female patients who underwent axillary dissection. The puncture success rates were 74.3%, 91.4%, and 97.1% for three sequential groups (P = .010). In diagnosing LN metastasis, the sensitivity, specificity, and accuracy values of LCEUS-guided FNA were 89.7%, 100%, and 95.7%, respectively. In predicting axillary metastasis, the sensitivity, specificity, and accuracy values of LCEUS-guided FNA were 81.4%, 100%, and 91.3%, respectively. CONCLUSIONS: The microinvasive LCEUS-guided FNA of one lymph node can be an accurate method and may help predict axillary metastasis in patients with breast cancer. ADVANCES IN KNOWLEDGE: This study presented that LCEUS combined with FNA would be practical in clinic. The characters of LCEUS could indicate the suspicious LNs and promote the accuracy in predicting axillary metastasis.

Association of AST/ALT ratio with 90-day outcomes in patients with acute exacerbation of chronic liver disease: a prospective multicenter cohort study in China.

Background and aim: A high aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is associated with liver injury in liver disease; however, no data exist regarding its relationship with 90-day prognosis in patients with acute exacerbation of chronic liver disease. Methods: In this study, 3,758 participants (955 with advanced fibrosis and 2,803 with cirrhosis) from the CATCH-LIFE cohort in China were included. The relationships between different AST/ALT ratios and the risk of adverse 90-day outcomes (death or liver transplantation) were determined in patients with cirrhosis or hepatitis B virus (HBV)-associated advanced fibrosis, respectively. Results: In the patients with HBV-associated advanced fibrosis, the risk of 90-day adverse outcomes increased with AST/ALT ratio; after adjusting for all confounding factors, the risk of adverse 90-day outcomes was the highest when AST/ALT ratio was more than 1.08 (OR = 6.91 [95% CI = 1.789-26.721], p = 0.005), and the AST/ALT ratio of >1.9 accelerated the development of adverse outcomes. In patients with cirrhosis, an AST/ALT ratio > 1.38 increased the risk of adverse 90-day outcomes in all univariables (OR = 1.551 [95% CI = 1.216-1.983], p < 0.001) and multivariable-adjusted analyses (OR = 1.847 [95% CI = 1.361-2.514], p < 0.001), and an elevated AST/ALT ratio (<2.65) accelerated the incidence of 90-day adverse outcomes. An AST/ALT ratio of >1.38 corresponded with a more than 20% incidence of adverse outcomes in patients with cirrhosis. Conclusion: The AST/ALT ratio is an independent risk factor for adverse 90-day outcomes in patients with cirrhosis and HBV-associated advanced fibrosis. The cutoff values of the AST/ALT ratio could help clinicians monitor the condition of patients when making clinical decisions.

Fecal Immunochemical Testing and the Risk of Advanced Colorectal Neoplasia: A Difference-In-Difference Analysis.

PURPOSE: To evaluate the effectiveness of fecal immunochemical testing (FIT) in colorectal cancer screening. METHODS: We conducted a prospective cohort study among 5,598 participants age 40-74 years between 2012 and 2020 in Tianjin, China. Inverse probability weighting was adopted to adjust for potential imbalanced factors between groups. A Cox proportional hazards model was used to estimate the weighted associations between FIT screening and advanced colorectal neoplasia. A difference-in-difference (DID) model was adopted to compare the incidence rates of advanced colorectal neoplasia between groups. RESULTS: In DID analysis, the rate of incidence was reduced by 0.34 cases per person-years in the screening group as compared with the historical FIT screening group (rate ratio [RR], 0.08 [95% CI, 0.07 to 0.10]) and by 0.06 cases per person-years in the non-FIT screening group as compared with the historical non-FIT screening group (RR, 0.37 [95% CI, 0.29 to 0.48]; P < .001 for both comparisons), with a relative reduction of 0.28. Similar benefit effect from FIT screening was observed in sex and age subgroups. CONCLUSION: FIT screening was associated with a reduction in incidence density from advanced colorectal neoplasia.

The clinical courses of HBV-related acute-on-chronic liver failure and a multi-state model to predict disease evolution.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS: We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS: Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS: HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

N6 -methyladenosine-modified circRNA RERE modulates osteoarthritis by regulating ß-catenin ubiquitination and degradation.

OBJECTIVES: N6 -methyladenosine (m6A) is one of the most abundant internal RNA modifications. We investigated the role of m6A-modified circRERE in osteoarthritis (OA) and its mechanism. MATERIALS AND METHODS: CircRERE and IRF2BPL were screened by microarrays. The role of m6A-modification in circRERE was examined by methylated RNA precipitation and morpholino oligo (MOs) treatment. The axis of circRERE/miR-195-5p/IRF2BPL/ß-catenin was determined using flow cytometry, western blotting and immunofluorescence in human chondrocytes (HCs) and corroborated using a mouse model of destabilization of medial meniscus (DMM) with intra-articular (IA) injection of adeno-associated viruses (AAV). RESULTS: CircRERE was decreased in OA cartilage and chondrocytes compared with control. CircRERE downregulation was likely attributed to its increased m6A modification prone to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP in OA chondrocytes. MOs transfection targeting HRSP12 binding motifs in circRERE partially reversed decreased circRERE expression and increased apoptosis in HCs treated with IL-1ß for 6 h. CircRERE exerted chondroprotective effects by targeting miR-195-5p/IRF2BPL, thus regulating the ubiquitination and degradation of ß-catenin. CircRere (mouse homologue) overexpression by IA-injection of AAV-circRere into mice attenuated the severity of DMM-induced OA, whereas AAV-miR-195a-5p or AAV-sh-Irf2bpl reduced the protective effects. The detrimental effects of AAV-sh-Irf2bpl on DMM-induced OA were substantially counteracted by ICG-001, an inhibitor of ß-catenin. CONCLUSIONS: Our study is a proof-of-concept demonstration for targeting m6A-modified circRERE and its target miR-195-5p/IRF2BPL/ß-catenin as potential therapeutic strategies for OA treatment.

Human understandable thyroid ultrasound imaging AI report system - A bridge between AI and clinicians.

Artificial intelligence (AI) enables accurate diagnosis of thyroid cancer; however, the lack of explanation limits its application. In this study, we collected 10,021 ultrasound images from 8,079 patients across four independent institutions to develop and validate a human understandable AI report system named TiNet for thyroid cancer prediction. TiNet can extract thyroid nodule features such as texture, margin, echogenicity, shape, and location using a deep learning method conforming to the clinical diagnosis standard. Moreover, it offers excellent prediction performance (AUC 0.88) and provides quantitative explanations for the predictions. We conducted a reverse cognitive test in which clinicians matched the correct ultrasound images according to TiNet and clinical reports. The results indicated that TiNet reports (87.1% accuracy) were significantly easier to understand than clinical reports (81.6% accuracy; p < 0.001). TiNet can serve as a bridge between AI-based diagnosis and clinicians, enhancing human-AI cooperative medical decision-making.

Automated diagnosis and management of follicular thyroid nodules based on the devised small-dataset interpretable foreground optimization network deep learning: a multicenter diagnostic study.

BACKGROUND: Currently, follicular thyroid carcinoma (FTC) has a relatively low incidence with a lack of effective preoperative diagnostic means. To reduce the need for invasive diagnostic procedures and to address information deficiencies inherent in a small dataset, we utilized interpretable foreground optimization network deep learning to develop a reliable preoperative FTC detection system. METHODS: In this study, a deep learning model (FThyNet) was established using preoperative ultrasound images. Data on patients in the training and internal validation cohort ( n =432) were obtained from Ruijin Hospital, China. Data on patients in the external validation cohort ( n =71) were obtained from four other clinical centers. We evaluated the predictive performance of FThyNet and its ability to generalize across multiple external centers and compared the results yielded with assessments from physicians directly predicting FTC outcomes. In addition, the influence of texture information around the nodule edge on the prediction results was evaluated. RESULTS: FThyNet had a consistently high accuracy in predicting FTC with an area under the receiver operating characteristic curve (AUC) of 89.0% [95% CI 87.0-90.9]. Particularly, the AUC for grossly invasive FTC reached 90.3%, which was significantly higher than that of the radiologists (56.1% [95% CI 51.8-60.3]). The parametric visualization study found that those nodules with blurred edges and relatively distorted surrounding textures were more likely to have FTC. Furthermore, edge texture information played an important role in FTC prediction with an AUC of 68.3% [95% CI 61.5-75.5], and highly invasive malignancies had the highest texture complexity. CONCLUSION: FThyNet could effectively predict FTC, provide explanations consistent with pathological knowledge, and improve clinical understanding of the disease.

Integrated gene profiling of fine-needle aspiration sample improves lymph node metastasis risk stratification for thyroid cancer.

BACKGROUND: Lymph node metastasis risk stratification is crucial for the surgical decision-making of thyroid cancer. This study investigated whether the integrated gene profiling (combining expression, SNV, fusion) of Fine-Needle Aspiration (FNA) samples can improve the prediction of lymph node metastasis in patients with papillary thyroid cancer. METHODS: In this retrospective cohort study, patients with papillary thyroid cancer who went through thyroidectomy and central lymph node dissection were included. Multi-omics data of FNA samples were assessed by an integrated array. To predict lymph node metastasis, we built models using gene expressions or mutations (SNV and fusion) only and an Integrated Risk Stratification (IRS) model combining genetic and clinical information. Blinded histopathology served as the reference standard. ROC curve and decision curve analysis was applied to evaluate the predictive models. RESULTS: One hundred and thirty two patients with pathologically confirmed papillary thyroid cancer were included between 2016-2017. The IRS model demonstrated greater performance [AUC = 0.87 (0.80-0.94)] than either expression classifier [AUC = 0.67 (0.61-0.74)], mutation classifier [AUC = 0.61 (0.55-0.67)] or TIRADS score [AUC = 0.68 (0.62-0.74)] with statistical significance (p < 0.001), and the IRS model had similar predictive performance in large nodule [>1 cm, AUC = 0.88 (0.79-0.97)] and small nodule [≤1 cm, AUC = 0.84 (0.74-0.93)] subgroups. The genetic risk factor showed independent predictive value (OR = 10.3, 95% CI:1.1-105.3) of lymph node metastasis in addition to the preoperative clinical information, including TIRADS grade, age, and nodule size. CONCLUSION: The integrated gene profiling of FNA samples and the IRS model developed by the machine-learning method significantly improve the risk stratification of thyroid cancer, thus helping make wise decisions and reducing unnecessary extensive surgeries.

Mitochondrial transfer from bone mesenchymal stem cells protects against tendinopathy both in vitro and in vivo.

BACKGROUND: Although mesenchymal stem cells (MSCs) have been effective in tendinopathy, the mechanisms by which MSCs promote tendon healing have not been fully elucidated. In this study, we tested the hypothesis that MSCs transfer mitochondria to injured tenocytes in vitro and in vivo to protect against Achilles tendinopathy (AT). METHODS: Bone marrow MSCs and H2O2-injured tenocytes were co-cultured, and mitochondrial transfer was visualized by MitoTracker dye staining. Mitochondrial function, including mitochondrial membrane potential, oxygen consumption rate, and adenosine triphosphate content, was quantified in sorted tenocytes. Tenocyte proliferation, apoptosis, oxidative stress, and inflammation were analyzed. Furthermore, a collagenase type I-induced rat AT model was used to detect mitochondrial transfer in tissues and evaluate Achilles tendon healing. RESULTS: MSCs successfully donated healthy mitochondria to in vitro and in vivo damaged tenocytes. Interestingly, mitochondrial transfer was almost completely blocked by co-treatment with cytochalasin B. Transfer of MSC-derived mitochondria decreased apoptosis, promoted proliferation, and restored mitochondrial function in H2O2-induced tenocytes. A decrease in reactive oxygen species and pro-inflammatory cytokine levels (interleukin-6 and -1ß) was observed. In vivo, mitochondrial transfer from MSCs improved the expression of tendon-specific markers (scleraxis, tenascin C, and tenomodulin) and decreased the infiltration of inflammatory cells into the tendon. In addition, the fibers of the tendon tissue were neatly arranged and the structure of the tendon was remodeled. Inhibition of mitochondrial transfer by cytochalasin B abrogated the therapeutic efficacy of MSCs in tenocytes and tendon tissues. CONCLUSIONS: MSCs rescued distressed tenocytes from apoptosis by transferring mitochondria. This provides evidence that mitochondrial transfer is one mechanism by which MSCs exert their therapeutic effects on damaged tenocytes.