High Risk Of Disease Progression Research Articles

CD71 mesangial IgA1 receptor and the progression of IgA nephropathy

The transferrin receptor (CD71) is known as a receptor for IgA1 on mesangial cells, but the role of CD71 in IgA nephropathy (IgAN) is unknown. We studied clinical implication of mesangial CD71 in 282 patients with biopsy-proven IgAN (2005-2018). The transcript and protein expression of glomerular CD71 was determined by real-time polymerase chain reaction and immunohistochemistry. Ten subjects with microscopic hematuria only and no evidence of histologic abnormalities on kidney biopsy were considered as controls. Human mesangial cells (HMCs) were treated with sera from IgAN patients and expression levels of CD71 and inflammatory cytokine markers were compared according to disease status. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate from the baseline value. During a mean follow up of 53.5 (18.3-75.9) months, 80 (28.4%) patients developed disease progression. The mRNA expression of CD71 was significantly higher in progressors than in nonprogressors (P = 0.001). Among the Oxford classification scores, patients with M1 had significantly higher CD71 expression levels than those with M0. In a multivariable Cox model, elevated transcript levels of CD71 were significantly associated with 4.32-fold higher risk of disease progression (P = 0.009). Furthermore, CD71 expression levels independently predicted the increase in proteinuria of ≥50% from the baseline (P = 0.03). Finally, HMCs treated with sera from IgAN patients with the higher Oxford score (M1E1S1T0) more increased the mRNA expression of CD71 and inflammatory markers than those with sera from negative score (M0E0S0T0). However, silencing CD71 significantly reduced expression levels of the inflammatory cytokine genes. Our results show that mesangial CD71 is significantly associated with disease progression and may play a biologic role in IgAN.

Risk of Metformin in Patients With Type 2 Diabetes With COVID-19: A Preliminary Retrospective Report.

The current outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has spread across the world. No specific antiviral agents have been adequately evidenced for the treatment of coronavirus disease 2019 (COVID‐19). Although metformin has been recommended as a host‐directed therapy for COVID‐19, there are some opposite views. The effects of metformin on the disease severity of patients with COVID‐19 with diabetes during hospitalization remains unclear. This study aimed to determine the effect of metformin on disease severity. We enrolled 110 hospitalized patients with COVID‐19 with diabetes prescribed either metformin or non‐metformin hypoglycemic treatment for a case‐control study. The primary outcome was the occurrence of life‐threatening complications. There were no differences between the two groups in age, sex, comorbidities, and clinical severity at admission. Blood glucose and lactate dehydrogenase levels of the metformin group were higher than those of the non‐metformin group at admission. Other laboratory parameters at admission and treatments after admission were not different between the two groups. Strikingly, the percentage of patients who experienced life‐threatening complications was significantly higher in the metformin group (28.6% (16/56) vs. 7.4% (4/54), P = 0.004). Antidiabetic therapy with metformin was associated with a higher risk of disease progression in patients with COVID‐19 with diabetes during hospitalization (adjusted odds ratio = 3.964, 95% confidence interval 1.034–15.194, P = 0.045). This retrospective analysis suggested a potential safety signal for metformin, the use of which was associated with a higher risk of severe COVID‐19. We propose that metformin withdrawal in patients with COVID‐19 be considered to prevent disease progression.

S0984 Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial

INTRODUCTION: Primary biliary cholangitis (PBC) is a rare, progressive autoimmune liver disease that leads to fibrosis, cirrhosis, and liver transplantation. PBC primarily affects females, but male patients and those with earlier age at diagnosis are at high risk for disease progression. Obeticholic acid (OCA) is approved as second-line treatment of PBC in patients nonresponsive or intolerant to ursodeoxycholic acid. The efficacy and safety of 12-month OCA treatment in patients with PBC was previously demonstrated in the POISE trial.1 We report the long-term efficacy and safety of OCA for more than 5 years in demographic patient subgroups from the POISE trial. METHODS: POISE was a randomized, double-blind, placebo-controlled, 12-month, phase 3 trial evaluating the efficacy and safety of OCA 5–10 mg or 10 mg vs placebo in patients with PBC. This was followed by a 5-year open-label extension (OLE) study during which all patients received OCA. The current analysis evaluated efficacy and safety outcomes in patient subgroups based on sex (male vs female), median age at study entry (≤55 years vs > 55 years), and median age at diagnosis (≤47.5 years vs > 47.5 years). Assessments included changes from OCA baseline in clinical laboratory tests and adverse events (AEs). Paired t-tests assessed within group comparisons. RESULTS: A total of 193 patients were included in the OLE study (median exposure: 5.4 y). In the OLE analysis, significant decreases in mean alkaline phosphatase (ALP) values were observed from OCA baseline for each subgroup from month 3 through month 72 (Figure 1). Similar trends were observed for other key markers of cholestasis and hepatic damage in each subgroup (Table 1). AEs were consistent with previous OCA studies. Over the course of six years of study conduct, 69%–79% of patients reported a pruritus event. CONCLUSION: These findings provide additional information on OCA safety and efficacy in various demographic patient subgroups. Treatment with OCA resulted in improvements in ALP, ALT, AST, and GGT values in patients with PBC in all demographic subgroups assessed. In the OLE, improvements in ALP were achieved by 3 months after OCA treatment initiation and were sustained after 5 years; these are important findings given the progressive nature of the disease.Figure 1Table 1

The Prognostic Effect of Metastatic Lymph Node Ratio in Operated Gastric Cancer Patients

To assess the prognostic importance of metastatic lymph node ratio (MLNR) in operated gastric cancer patients. Observational study. Health Sciences University, Yildirim Beyazit Diskapi Training and Research Hospital, Department of General Surgery, Ankara, Turkey, between January 2014 and March 2019. Initially, record of a total of 171 patients, operated for gastric cancer, were retrieved. Inclusion criteria involved having gastric adenocarcinoma, undergoing curative-intent surgery, absence of neoadjuvant chemotherapy, dissection of ≥15 lymph nodes, negative surgical margins, and no mortality within the first 30 days after surgery. Thirty patients were excluded for various reasons. Thus, clinicopathological features and prognostic factors including MLNR on overall and disease-free survival (DFS) were evaluated for the remaining 141 patients. The median age of the 141 patients was 63 years (IQR: 54 - 72 years). The median MLNR was 0.18 (IQR: 0 - 0.47). The cut-off value with highest sensitivity and specificity was determined as 0.25 (area under the curve (AUC); 0.724, CI 95%; 0.639-0.808, p <0.001) in ROC curve analysis. Multivariable Cox regression analysis showed MLNR and perineural invasion (PNI) as independent prognostic factors. Patients with MLNR >0.25 had a 2.39-fold higher risk of disease progression, and 3.76-fold higher risk of shorter survival. The study contributed to the literature that MLNR is practical and useful as an independent prognostic factor predicting survival even better than tumor/node/metastasis (TNM) staging system. Key Words: Gastric cancer, Metastatic lymph node ratio, Prognostic factor, Surgery.

Development of a nomogram for the prediction of periodontal tooth loss using the staging and grading system: A long-term cohort study.

To develop and internally validate a nomogram built on a multivariate prediction model including parameters from the new classification of periodontal diseases, able to predict, at baseline, the occurrence of tooth loss due to periodontal reason (TLP). A total of 315 individuals diagnosed with periodontal disease and receiving a minimum of one annual supportive periodontal therapy visit were included in the study. Patients were staged and graded based upon baseline data. The population was divided into a development (254 patients) and a validation (61 patients) cohort to allow subsequent temporal validation of the model. According to the TLP at the 10-year follow-up, patients were categorized as "low tooth loss" (≤ 1 TLP) or "high tooth loss" (≥ 2 TLP). Bootstrap internal validation was performed on the whole data set to calculate an optimism-corrected estimate of performance. The generated nomogram showed a strong predictive capability (AUC=0.81) and good calibration with an intercept=0 and slope=1. These findings were confirmed by internal validation using bootstrapping (average bootstrap AUC=0.83). The clinical implementation of the present nomogram guides the prediction of patients with high risk of disease progression and subsequent tooth loss for personalized care.

Computer Extracted Features from Initial H&E Tissue Biopsies Predict Disease Progression for Prostate Cancer Patients on Active Surveillance.

Simple SummaryActive surveillance (AS) prostate cancer patients suffer from a lower quality of life, increased risk of anxiety and depression, and an increased risk of disease progression compared to patients who opt for curative treatment. The current inclusion criteria for AS patients is unable to accurately identify patients with increased risk of progression, and therefore there is a need for a risk stratification technique that can identify patients with a higher risk of disease progression. In this work, we leverage quantitative histomorphometric (QH) features describing nuclear position, shape, orientation, and clustering from initial H&E biopsy images to accurately identify AS-eligible patients who are at high risk for disease progression. Our findings indicate that QH features were correlated with the risk of clinical progression in AS-eligible patients and was able to out-perform judgements based on clinical variables such as Gleason score and pro-PSA.In this work, we assessed the ability of computerized features of nuclear morphology from diagnostic biopsy images to predict prostate cancer (CaP) progression in active surveillance (AS) patients. Improved risk characterization of AS patients could reduce over-testing of low-risk patients while directing high-risk patients to therapy. A total of 191 (125 progressors, 66 non-progressors) AS patients from a single site were identified using The Johns Hopkins University’s (JHU) AS-eligibility criteria. Progression was determined by pathologists at JHU. 30 progressors and 30 non-progressors were randomly selected to create the training cohort D1 (n = 60). The remaining patients comprised the validation cohort D2 (n = 131). Digitized Hematoxylin & Eosin (H&E) biopsies were annotated by a pathologist for CaP regions. Nuclei within the cancer regions were segmented using a watershed method and 216 nuclear features describing position, shape, orientation, and clustering were extracted. Six features associated with disease progression were identified using D1 and then used to train a machine learning classifier. The classifier was validated on D2. The classifier was further compared on a subset of D2 (n = 47) against pro-PSA, an isoform of prostate specific antigen (PSA) more linked with CaP, in predicting progression. Performance was evaluated with area under the curve (AUC). A combination of nuclear spatial arrangement, shape, and disorder features were associated with progression. The classifier using these features yielded an AUC of 0.75 in D2. On the 47 patient subset with pro-PSA measurements, the classifier yielded an AUC of 0.79 compared to an AUC of 0.42 for pro-PSA. Nuclear morphometric features from digitized H&E biopsies predicted progression in AS patients. This may be useful for identifying AS-eligible patients who could benefit from immediate curative therapy. However, additional multi-site validation is needed.

Association of endothelin-1 and cell surface adhesion molecules levels in patients with systemic sclerosis

Abstract Objectives Endothelin-1 (ET-1) has been implicated in the pathogenesis of inflammatory and fibrotic diseases, including systemic sclerosis. In addition to modulating vascular tone and extracellular matrix turnover, ET-1 up-regulates cell surface adhesion molecules–intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).The aim of the study was to evaluate the diagnostic value of the detection of ET-1, VCAM-1 and ICAM-1 in the diagnosis of systemic sclerosis. Methods A total of 30 patients with systemic sclerosis from Vilnius University Hospital Santaros Clinics were included in the study. Serum levels of ICAM-1, VCAM-1 and ET-1 were assessed by enzyme immunoassay. Results ET-1 concentration was associated with VCAM-1 concentration (r=0.687; p&lt;0.001). No associations between ET-1 and ICAM-1 concentrations were detected. Depending on the duration of the disease no significant differences in the concentrations of ET-1, ICAM-1 and VCAM-1 were detected. Conclusions The results of this study indicated that ET-1 and VCAM-1 may be assessed together as markers of inflammation and the identification of patients at high risk for disease progression.

Presence of constipation predicts the therapeutic efficacy of pembrolizumab in metastatic urothelial cancer patients.

To study bowel function in urothelial cancer patients treated with pembrolizumab and to assess its association with treatment efficacy. This retrospective study was analyzed for patients with metastatic urothelial cancer who received immune checkpoint inhibitor treatment between December 2017 and June 2019 at Nagoya University and affiliated hospitals in Japan. The association between bowel dysfunction (defined as constipation or need for laxatives) and treatment efficacy was investigated. We retrospectively enrolled 73 patients with metastatic urothelial cancer who received immune checkpoint inhibitor treatment. All patients received pembrolizumab at 200mg per bodyweight administered intravenously every 3weeks. Performance status was 0-1 in 58 patients (79.5%), and liver metastasis was detected in 22 patients (30.1%). The median age was 72years (range 40-89years). A total of 45 patients had constipation. The median progression-free survival and overall survival from the start of immune checkpoint inhibitor treatment was 4.0months (95% confidence interval 1.0-17.3) and 6.6months (95% confidence interval 1.0-18.0), respectively. Patients with constipation had a significantly higher risk of disease progression (P=0.005). There was no significant association between constipation and overall survival (P=0.131). However, complete response was observed among two patients treated with immune checkpoint inhibitor, both of whom did not present constipation. The presence of constipation might be a prognostic factor for urothelial cancer patients undergoing immune checkpoint inhibitor treatment.

Baseline SUVmax of 18F-FDG PET-CT indicates prognosis of extranodal natural killer/T-cell lymphoma.

To evaluate the prognostic value of the baseline SUVmax of F-FDG PET-CT in extranodal natural killer/T-cell lymphoma (NKTCL) patients.From January 2010 to December 2015, 141 extranodal NKTCL patients with staging F-FDG PET-CT scan were divided into two group based on SUVmax cutoff value obtained from operating characteristic (ROC) curves. All the patients received radiotherapy, chemotherapy or chemoradiation. Survival analysis was performed on the basis of SUVmax.The median baseline SUVmax of the tumors was 11.67 (range 2.6-34.6). The ROC curves showed that the optimal cutoff of the baseline SUVmax was 9.65. The patients were divided into two groups: low SUV group (SUVmax < 9.65) and high SUV group (SUVmax ≥ 9.65). Patients in high SUV group were more likely to have invasive disease outside the nasal cavity (P < .001), poorer ECOG scores (P = .012) and higher LDH levels (P = .034). The univariate survival analyses indicated that high SUVmax was a poor prognostic factor for overall survival (OS, P = .038), progression free survival (PFS, P = .006) and distant relapse free survival (DRFS, P = .001), but not for local recurrence free survival (LRFS, P > .05). These results were consistent with that of the survival analyses using the Kaplan-Meier method. The multivariate survival analyses showed that the baseline SUVmax was no longer a prognostic factor for OS (HR 1.99, 95% CI 0.81-4.88, P = .135), but it still indicated worse PFS (HR 2.6, 95% CI 1.24-5.46, P = .012) and DRFS (HR 4.58, 95% CI 1.83-11.46, P = .001) independent of other variables.For extranodal NKTCL patients, a higher baseline SUVmax of F-FDG PET-CT was associated with more aggressive clinical features. An SUVmax ≥ 9.65 was an independent poor prognostic factor for DRFS and PFS. Thus, the baseline SUVmax may be a valuable tool to help identify patients with a high risk of disease progression.

External validation of International Prognostic Score for asymptomatic early stage chronic lymphocytic leukaemia and proposal of an alternative score.

Most patients with chronic lymphocytic leukaemia (CLL) are nowadays diagnosed without any symptoms and do not require therapy. A prognostic score identifying patients within this large group who are at high risk of disease progression would be highly beneficial. The recently published International Prognostic Score for Early asymptomatic patients (IPS-E) uses combination of absolute lymphocyte count (ALC) >15×109 /l, palpable lymphadenopathy, and unmutated immunoglobulin heavy-chain variable-region (IGHV) gene to predict the time to first-line therapy (TTFT). Patients at low, intermediate, and high risk had estimated 5-year TTFT of 8%, 28%, and 61%. We performed an external validation of the IPS-E score using an unselected, consecutive group of 130 Binet A patients. The 5-year TTFT was 11%, 36%, and 78% (C-statistic 0·74). Furthermore, we propose an alternative system (AIPS-E) using cytogenetic aberrations instead of palpable lymphadenopathy. This system yielded 5-year TTFT of 14%, 40%, and 72%. These results were externally validated in 388 Binet A patients from five Czech centres; the 5-year TTFT was 16%, 37%, and 80% (C-statistic 0·74). In conclusion, we have successfully validated the IPS-E score for patients with early stage CLL. In addition, we propose a modified scoring system, the AIPS-E, combining IGHV, fluorescence in situ hybridisation, and ALC.

Long-Term Imaging Evolution and Clinical Prognosis Among Patients With Acute Penetrating Aortic Ulcers: A Retrospective Observational Study.

BackgroundAcute penetrating aortic ulcers (PAUs) are reported to dynamically evolve into different clinical outcomes ranging from regression to aortic rupture, but no practice guidelines are available in China.Methods and ResultsAll 109 patients with acute PAUs were monitored clinically. At 30 days follow‐up, 31 patients (28.44%) suffered from aortic‐related adverse events, a composite of aortic‐related mortality, aortic dissection, or an enlarged ulcer. In addition, 7 (6.42%) patients had clinically related adverse events, including all‐cause mortality, cerebral stroke, nonfatal myocardial infarction, acute heart failure alone or acute exacerbation of chronic heart failure, acute renal failure, arrhythmia, and bleeding events. In the present study, the intervention criteria for the Chinese PAU population included a PAU diameter of 12.5 mm and depth of 9.5 mm. The multivariate analysis showed that an ulcer diameter >12.5 mm (hazard ratio [HR], 3.846; 95% CI, 1.561–9.476; P=0.003) and an ulcer depth >9.5 mm (HR, 3.359; 95% CI, 1.505–7.494; P=0.003) were each independent predictors of aortic‐related events.ConclusionsPatients with acute PAUs were at high risk for aortic‐related adverse events and clinically related adverse events within 30 days after onset. Patients with an ulcer diameter >12.5 mm or an ulcer depth >9.5 mm have a higher risk for disease progression, and early intervention may be recommended.

Clinical characteristics and risk factors of patients with severe COVID-19 in Jiangsu province, China: a retrospective multicentre cohort study

BackgroundCoronavirus Disease-2019 (COVID-19) pandemic has become a major health event that endangers people health throughout China and the world. Understanding the factors associated with COVID-19 disease severity could support the early identification of patients with high risk for disease progression, inform prevention and control activities, and potentially reduce mortality. This study aims to describe the characteristics of patients with COVID-19 and factors associated with severe or critically ill presentation in Jiangsu province, China.MethodsMulticentre retrospective cohort study of all individuals with confirmed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections diagnosed at 24 COVID-19-designated hospitals in Jiangsu province between the 10th January and 15th March 2020. Demographic, clinical, laboratory, and radiological data were collected at hospital admission and data on disease severity were collected during follow-up. Patients were categorised as asymptomatic/mild/moderate, and severe/critically ill according to the worst level of COVID-19 recorded during hospitalisation.ResultsA total of 625 patients, 64 (10.2%) were severe/critically ill and 561 (89.8%) were asymptomatic/mild/moderate. All patients were discharged and no patients died. Patients with severe/critically ill COVID-19 were more likely to be older, to be single onset (i.e. not belong to a cluster of cases in a family/community, etc.), to have a medical history of hypertension and diabetes; had higher temperature, faster respiratory rates, lower peripheral capillary oxygen saturation (SpO2), and higher computer tomography (CT) image quadrant scores and pulmonary opacity percentage; had increased C-reactive protein, fibrinogen, and D-dimer on admission; and had lower white blood cells, lymphocyte, and platelet counts and albumin on admission than asymptomatic/mild/moderate cases. Multivariable regression showed that odds of being a severe/critically ill case were associated with age (year) (OR 1.06, 95%CI 1.03–1.09), lymphocyte count (109/L) (OR 0.25, 95%CI 0.08–0.74), and pulmonary opacity in CT (per 5%) on admission (OR 1.31, 95%CI 1.15–1.51).ConclusionsSevere or critically ill patients with COVID-19 is about one-tenths of patients in Jiangsu. Age, lymphocyte count, and pulmonary opacity in CT on admission were associated with risk of severe or critically ill COVID-19.

A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study

Non-invasive tests that can identify patients with non-alcoholic steatohepatitis (NASH) at higher risk of disease progression are lacking. We report the development and validation of a blood-based diagnostic test to non-invasively rule in and rule out at-risk NASH (defined as non-alcoholic fatty liver disease [NAFLD] activity score [NAS] ≥4 and fibrosis stage ≥2). In this prospective derivation and global validation study, blood samples, clinical data, and liver biopsy results from three independent cohorts with suspected NAFLD were used to develop and validate a non-invasive blood-based diagnostic test, called NIS4. Derivation was done in the discovery cohort, which comprised 239 prospectively recruited patients with biopsy-confirmed NASH (NAFLD NAS ≥3; fibrosis stage 0-3) from the international GOLDEN-505 phase 2b clinical trial. A complete matrix based on 23 variables selected for univariate association with the presence of at-risk NASH and avoiding high multi-collinearity was used to derive the model in a bootstrap-based process that minimised the Akaike information criterion. The overall diagnostic performance of NIS4 was externally validated in two independent cohorts: RESOLVE-IT diag and Angers. The RESOLVE-IT diag cohort comprised the first 475 patients screened for potential inclusion into the RESOLVE-IT phase 3 clinical trial. Angers was a retrospective cohort of 227 prospectively recruited patients with suspected NAFLD and clinical risk factors for NASH or fibrosis stage 2 or more according to abnormal elastography results or abnormal liver biochemistry. Both external validation cohorts were independently analysed and were combined into a pooled validation cohort (n=702) to assess clinical performance of NIS4 and other non-invasive tests. The derived NIS4 algorithm comprised four independent NASH-associated biomarkers (miR-34a-5p, alpha-2 macroglobulin, YKL-40, and glycated haemoglobin; area under the receiver operating characteristics curve [AUROC] 0·80, 95% CI 0·73-0·85), and did not require adjustment for age, sex, body-mass index (BMI), or aminotransferase concentrations. Clinical cutoffs were established within the discovery cohort to optimise both rule out and rule in clinical performance while minimising indeterminate results. NIS4 was validated in the RESOLVE-IT diag cohort (AUROC 0·83, 95% CI 0·79-0·86) and the Angers cohort (0·76, 0·69-0·82). In the pooled validation cohort, patients with a NIS4 value less than 0·36 were classified as not having at-risk NASH (ruled out) with 81·5% (95% CI 76·9-85·3) sensitivity, 63·0% (57·8-68·0) specificity, and a negative predictive value of 77·9% (72·5-82·4), whereas those with a NIS4 value of more than 0·63 were classified as having at-risk NASH (ruled in) with 87·1% (83·1-90·3) specificity, 50·7% (45·3-56·1) sensitivity, and a positive predictive value of 79·2% (73·1-84·2). The diagnostic performance of NIS4 within the external validation cohorts was not influenced by age, sex, BMI, or aminotransferase concentrations. NIS4 is a novel blood-based diagnostic that provides an effective way to non-invasively rule in or rule out at-risk NASH in patients with metabolic risk factors and suspected disease. Use of NIS4 in clinical trials or in the clinic has the potential to greatly reduce unnecessary liver biopsies in patients with lower risk of disease progression. Genfit.

Development of prognostic model for patients at CKD stage 3a and 3b in South Central China using computational intelligence.

Chronic kidney disease (CKD) stage 3 was divided into two subgroups by eGFR (45mL/ min 1.73m2). There is difference in prevalence of CKD, racial differences, economic development, genetic, and environmental backgrounds between China and Western countries. We used a computational intelligence model (CKD stage 3 Modeling, CSM) to distinguish CKD stage 3 with CKD stage 3a/3b by data distribution rules, pearson correlation coefficient (PCC), spearman correlation (SCC) analysis, logistic regression (LR), random forest (RF), support vector machine (SVM), and neural network (Nnet) to develop Prognostic Model for patients with CKD stage 3a/3b in South Central China. Furthermore, we used RF to discover risk factors of progression of CKD stage 3a and 3b to CKD stage 5. 1090 cases of CKD stage 3 patients in Xiangya Hospital were collected. Among them, 455 patients progressed to CKD stage 5 in a median follow-up of 4years (IQR 4.295, 4.489). We found that the common risk factors for progression of CKD stage 3a/3b to CKD stage 5 included albumin, creatinine, total protein, etc. Proteinuria, direct bilirubin, hemoglobin, etc. accounted for the progression from stage CKD stage 3a to stage 5. The risk factors for CKD stage 3b progression to stage 5 included low-density lipoprotein cholesterol, diabetes, eosinophil percentage, etc. CONCLUSIONS: CSM could be used as a point-of-care test to screen patients at high risk for disease progression, might allowing individualized therapeutic management.

MiR-181a overexpression predicts the poor treatment response and early-progression of serous ovarian cancer patients.

Ovarian cancer (OC) remains a leading cause of gynecological cancer-related death worldwide, characterized by poor 5-year survival. Molecular markers could serve as crucial tools of personalized prognosis and therapy. Herein, we present miR-181a as novel predictor of OC prognosis, using five independent OC cohorts. In particular, a screening (n = 81) and an institutionally independent validation (n = 100, OVCAD multicenter study) serous OC (SOC) cohorts were analyzed. Bagnoli et al (2016) OC179 (n = 124) to OC133 (n = 100) and TCGA (n = 489) served as external validation cohorts. Patients' survival and disease progression were assessed as clinical endpoint events. Bootstrap analysis was performed for internal validation and decision curve analysis was utilized to evaluate clinical benefit. miR-181a overexpression was unveiled as powerful and independent molecular predictor of patients' poor survival and higher risk for disease progression after debulking surgery and platinum-based chemotherapy. Analysis of the OVCAD institutionally independent cohort, as well as of Bagnoli et al. and TCGA external cohorts further confirmed the unfavorable prognostic nature of miR-181a overexpression in SOC. Strikingly, multivariate prognostic models incorporating miR-181a with established disease markers clearly improved patients' risk-stratification and offered superior clinical benefit in OC prognostication. Conclusively, miR-181a evaluation could augment prognostic accuracy and support precision medicine decisions in OC.

Comparison of MAFLD and NAFLD diagnostic criteria in real world.

Metabolic associated fatty liver disease (MAFLD) is a novel concept proposed in 2020, the utility of which has not been tested and validated in real world. We aimed to compare the characteristics of MAFLD and non-alcoholic fatty liver disease (NAFLD). The data was retrieved from the third National Health and Nutrition Examination Surveys of the United States, which is an unbiased survey dataset and frequently used for the study of fatty liver disease. A total of 13 083 cases with completed ultrasonography and laboratory data were identified from the NHANES III database. MAFLD was diagnosed in 4087/13 083 (31.24%) participants, while NAFLD in 4347/13 083 (33.23%) amongst the overall population and 4347/12 045 (36.09%) in patients without alcohol intake and other liver diseases. Compared with NAFLD, MAFLD patients were significantly older, had higher BMI level, higher proportions of metabolic comorbidities (diabetes, hypertension) and higher HOMA-IR, lipid and liver enzymes. MAFLD patients with alcohol consumption were younger than those without, and more likely to be male. They had less metabolic disorder but higher liver enzymes. There were more cases with advance fibrosis in MAFLD patients with alcohol consumption. MAFLD definition is more practical for identifying patients with fatty liver disease with high risk of disease progression.

Histopathological distinction of non-invasive and invasive bladder cancers using machine learning approaches

BackgroundOne of the most challenging tasks for bladder cancer diagnosis is to histologically differentiate two early stages, non-invasive Ta and superficially invasive T1, the latter of which is associated with a significantly higher risk of disease progression. Indeed, in a considerable number of cases, Ta and T1 tumors look very similar under microscope, making the distinction very difficult even for experienced pathologists. Thus, there is an urgent need for a favoring system based on machine learning (ML) to distinguish between the two stages of bladder cancer.MethodsA total of 1177 images of bladder tumor tissues stained by hematoxylin and eosin were collected by pathologists at University of Rochester Medical Center, which included 460 non-invasive (stage Ta) and 717 invasive (stage T1) tumors. Automatic pipelines were developed to extract features for three invasive patterns characteristic to the T1 stage bladder cancer (i.e., desmoplastic reaction, retraction artifact, and abundant pinker cytoplasm), using imaging processing software ImageJ and CellProfiler. Features extracted from the images were analyzed by a suite of machine learning approaches.ResultsWe extracted nearly 700 features from the Ta and T1 tumor images. Unsupervised clustering analysis failed to distinguish hematoxylin and eosin images of Ta vs. T1 tumors. With a reduced set of features, we successfully distinguished 1177 Ta or T1 images with an accuracy of 91–96% by six supervised learning methods. By contrast, convolutional neural network (CNN) models that automatically extract features from images produced an accuracy of 84%, indicating that feature extraction driven by domain knowledge outperforms CNN-based automatic feature extraction. Further analysis revealed that desmoplastic reaction was more important than the other two patterns, and the number and size of nuclei of tumor cells were the most predictive features.ConclusionsWe provide a ML-empowered, feature-centered, and interpretable diagnostic system to facilitate the accurate staging of Ta and T1 diseases, which has a potential to apply to other types of cancer.

Non-alcoholic fatty liver disease: a metabolic burden promoting atherosclerosis.

Non-alcoholic fatty liver disease (NAFLD) has become the fastest growing chronic liver disease, with a prevalence of up to 25% worldwide. Individuals with NAFLD have a high risk of disease progression to cirrhosis, hepatocellular carcinoma (HCC), and liver failure. With the exception of intrahepatic burden, cardiovascular disease (CVD) and especially atherosclerosis (AS) are common complications of NAFLD. Furthermore, CVD is a major cause of death in NAFLD patients. Additionally, AS is a metabolic disorder highly associated with NAFLD, and individual NAFLD pathologies can greatly increase the risk of AS. It is increasingly clear that AS-associated endothelial cell damage, inflammatory cell activation, and smooth muscle cell proliferation are extensively impacted by NAFLD-induced systematic dyslipidemia, inflammation, oxidative stress, the production of hepatokines, and coagulations. In clinical trials, drug candidates for NAFLD management have displayed promising effects for the treatment of AS. In this review, we summarize the key molecular events and cellular factors contributing to the metabolic burden induced by NAFLD on AS, and discuss therapeutic strategies for the improvement of AS in individuals with NAFLD.

Early Warning Indicators of Severe COVID-19: A Single-Center Study of Cases From Shanghai, China.

Background: Patients with severe novel coronavirus disease (COVID-19) can likely develop comorbidities, which can lead to irreversible organ damage and, eventually, death. However, early indicators of disease progression remain unclear. This study aimed to identify early indicators of disease progression to provide a basis for improved prognostic prediction and disease management.Methods: We examined 53 recovered adult COVID-19 patients who were treated at Shanghai Public Health Clinical Center between January 20, 2020, and February 20, 2020. The patients were categorized into the following four groups according to their condition at admission: mild condition (n = 3), moderate (n = 41), severe (n = 7), and critical (n = 2). They were also categorized according to disease progression as mild or moderate conditions that remained stable (n = 26), moderate disease that progressed to severe condition (n = 18), and continuously severe or critical (n = 9). We then focused on investigating the differences in the epidemiological and laboratory indicators between remained stable cases and progressed to severe condition cases.Results: Mild or moderate patients were younger than severe or critical patients. The number of patients with shortness of breath and underlying diabetes and heart disease at admission was higher in the severe or critical group. This group also showed considerably lower or higher values in 28 laboratory indicators. In addition, mild and moderate patients who remained stable were younger than moderate patients progressing to severe disease. Men had a higher risk of disease progression. Patients who progressed had either higher or lower values in 11 laboratory indicators. Survival curve analysis showed that age, procalcitonin, D-dimer, serum C-reactive protein, lactate dehydrogenase, lymphocytes, neutrophils, CD4%, and CD4/CD8 ratio were significant predictors of progression to severe disease.Conclusions: Lactate dehydrogenase, procalcitonin, etc. are early warning indicators of severe COVID-19. Age (>64 years), shortness of breath, past histories of diabetes and heart disease, and abnormality in 28 other indicators at admission are indicative of severe or progression toward severe COVID-19. Meanwhile, abnormalities in 11 indicators and an abnormal coagulation function index at admission are risk factors for progression to severe disease.

Racial and Ethnic Disparities in Disease Severity on Admission Chest Radiographs among Patients Admitted with Confirmed Coronavirus Disease 2019: A Retrospective Cohort Study.

BackgroundDisease severity on chest radiographs (CXR) has been associated with higher risk of disease progression and adverse outcomes from COVID-19. Few studies have evaluated COVID-19-related racial/ethnic disparities in radiology.PurposeTo evaluate whether Non-White minority patients hospitalized with confirmed COVID-19 infection presented with increased severity on admission CXR compared with White/Non-Hispanic patients.MethodsSingle-institution, retrospective cohort study approved by the IRB. Patients hospitalized with confirmed COVID-19 infection (3/27/20-4/10/20) were identified using the electronic medical record (EMR) (n=326, mean age: 59 years (SD: 17 years), M:F (188:138). Primary outcome was severity of lung disease on admission CXR, measured by modified Radiographic Assessment of Lung Edema (mRALE) score. Secondary outcome was a composite adverse clinical outcome of intubation, ICU admission, or death. Primary exposure was racial/ethnic category: White/Non-Hispanic versus Non-White [i.e., Hispanic, Black, Asian, Other]. Multivariable linear regression analyses were performed to evaluate the association between mRALE scores and race/ethnicity.ResultsNon-White patients had significantly higher mRALE scores (median 6.1, 95% CI 5.4–6.7) compared with White/Non-Hispanic patients (median 4.2, 95% CI 3.6–4.9) (unadjusted average difference 1.8, 95% CI 0.9–2.8, p<0.01). For both White (Adjusted HR, 1.3, 95%CI 1.2-1.4, p<0.001) and Non-White patients (Adjusted HR 1.2, 95%CI 1.1-1.3, p<0.001), increasing mRALE scores were associated with a higher likelihood of experiencing composite adverse outcome with no evidence of interaction (p = 0.16). Multivariable linear regression analyses demonstrated that Non-White patients presented with higher mRALE scores on admission CXR versus White/Non-Hispanic patients (adjusted average difference 1.6, 95% CI 0.5–2.7, p<0.01). Adjustment for hypothesized mediators revealed that the association between race/ethnicity and mRALE scores was mediated by limited English proficiency (p<0.01).ConclusionNon-White patients hospitalized with COVID-19 infection were more likely to present with higher severity of disease on admission CXR than White/Non-Hispanic patients, and increased severity was associated with worse outcomes for all patients.