Genetic association of serum lipids and lipid-modifying targets with endometriosis: Trans-ethnic Mendelian-randomization and mediation analysis.

BACKGROUND: Prior observational research identified dyslipidemia as a risk factor for endometriosis (EMS) but the causal relationship remains unestablished due to inherent study limitations. METHODS: Genome-wide association study data for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC) from European (EUR) and East Asian (EAS) ancestries were sourced from the Global Lipids Genetics Consortium. Multi-ancestry EMS data came from various datasets. Univariable Mendelian randomization (MR) examined causal links between serum lipids and EMS. Multivariable and mediation MR explored the influence of seven confounding factors and mediators. Drug-target MR investigates the association between lipid-lowering target genes identified in positive results and EMS. The primary method was inverse-variance weighted (IVW), with replication datasets and meta-analyses reinforcing causal associations. Sensitivity analyses included false discovery rate (FDR) correction, causal analysis using summary effect estimates (CAUSE), and colocalization analysis. RESULTS: IVW analysis in EUR ancestry showed a significant causal association between TG and increased EMS risk (OR = 1.112, 95% CI 1.033-1.198, P = 5.03×10-3, PFDR = 0.03), supported by replication and meta-analyses. CAUSE analysis confirmed unbiased results (P < 0.05). Multivariable and mediation MR revealed that systolic blood pressure (Mediation effect: 7.52%, P = 0.02) and total testosterone (Mediation effect: 10.79%, P = 0.01) partly mediated this relationship. No causal links were found between other lipid traits and EMS (P > 0.05 & PFDR > 0.05). In EAS ancestry, no causal relationships with EMS were detected (P > 0.05 & PFDR > 0.05). Drug-target MR indicated suggestive evidence for the influence of ANGPTL3 on EMS mediated through TG (OR = 0.798, 95% CI 0.670-0.951, P = 0.01, PFDR = 0.04, PP.H4 = 0.85%). CONCLUSIONS: This MR study in EUR ancestry indicated an increased EMS risk with higher serum TG levels.

Consistency and diagnostic accuracy of 4 assays in the detection of the total and free prostate-specific antigen.

Background: The lack of interchangeability among prostate-specific antigen (PSA) assays causes difficulties in clinical interpretation. The currently available mainstream assays for PSA were based on Western populations, but it is not clear whether these assays yield different results in prostate cancer (PCa) screening in Chinese populations. Methods: A total of 163 men with a total PSA (tPSA) level of 2-10 µg/L scheduled for prostate biopsy were enrolled in this study. The levels of the tPSA and free PSA (fPSA) were detected by the Beckman (using the Hybritech calibration), Roche, Abbott, and Mindray (using the World Health Organization's calibration). Methodological comparison were performed according to EP9-A3 of the Clinical and Laboratory Standards Institute, USA. With pathological diagnosis as the gold standard, the predictive accuracy of the biomarkers was quantified as the area under the receiver operating characteristic curve (AUC) for each of the four methods. Results: A total of 32 PCa patients and 131 patients with benign prostate disease were included in this study. The tPSA levels detected by the Roche, Abbott, and Mindray showed good consistency with Beckman but not of the fPSA levels. Compared to the Beckman tPSA values, the measured values were 1.1% higher for Roche, 2.1% higher for Abbott, and 6.7% higher for Mindray. The fPSA levels measured by Roche, Abbott, and Mindray were 5.4% lower, 22.1% higher, and 4.6% higher than Beckman, respectively. When the tPSA was 4 ng/mL, the diagnostic performance (sensitivity, specificity, positive predictive value, negative predictive value, and missed diagnosis rate) was similar among these 4 assays. When the %fPSA was 16%, Abbott had the highest missed diagnosis rate (37.50%), while Mindray had a sensitivity of 81.25%, the highest negative predictive value (93.88%), and the lowest missed diagnosis rate (18.75%). Conclusions: When the tPSA level is 2-10 ng/mL, the Mindray, like the Roche and Abbott, has good consistency with the Beckman in detecting tPSA, which makes it possible to relieve the pressure of clinical interpretation. However, 4 assays using the same %fPSA cut-off may lead to diverse missed diagnosis rates for PCa screening in China.

Ontology Specific Alternative Splicing Changes in Alzheimer's Disease.

Alternative splicing (AS) is a common phenomenon and correlates with aging and aging-related disorders including Alzheimer's disease (AD). We aimed to systematically characterize AS changes in the cerebral cortex of 9-month-old APP/PS1 mice. The GSE132177 dataset was downloaded from GEO and ENA databases, aligned to the GRCm39 reference genome from ENSEMBL via STAR. Alternative 3'SS (A3SS), alternative 5'SS (A5SS), skipped exon (SE), retained intron (RI), and mutually exclusive exons (MXE) AS events were evaluated using rMATS, rmats2sashimiplot, and maser. Differential genes or transcripts were analyzed using the limma R package. Gene ontology analysis was performed with the clusterProfiler R package. A total of 60,705 raw counts of AS were identified, and 113 significant AS events were finally selected in accordance with the selection criteria: 1) average coverage >10 and 2) delta percent spliced in (ΔPSI) >0.1. SE was the most abundant AS event (61.95%), and RI was the second most abundant AS type (13.27%), followed by A3SS (12.39%), thereafter A5SS and MXE comprised of 12.39%. Interestingly, genes that experienced SE were enriched in histone acetyltransferase (HAT) complex, while genes spliced by RI were enriched in autophagy and those which experienced A3SS were enriched in methyltransferase activity revealed by GO analysis. In conclusion, we revealed ontology specific AS changes in AD. Our analysis provides novel pathological mechanisms of AD.

PRRT2 Mutation and Serum Cytokines in Paroxysmal Kinesigenic Dyskinesia.

OBJECTIVE: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder PRRT2 gene mutations have been reported to cause PKD. However, the pathophysiological mechanism of PKD remains unclear, and it is unknown whether an inflammatory response is involved in the occurrence of this disease. We aimed to investigate the symptomatology, genotype, and serum cytokines of patients with PKD. METHODS: We recruited 21 patients with PKD, including 7 with familial PKD and 14 with sporadic PKD. Their clinical features were investigated, and blood samples were collected, and PRRT2 mutations and cytokine levels were detected. RESULTS: The mean age at PKD onset was 12.3±2.2 years old. Dystonia was the most common manifestation of dyskinesia, and the limbs were the most commonly affected parts. All attacks were induced by identifiable kinesigenic triggers, and the attack durations were brief (<1 min). Four different mutations from 9 probands were identified in 7 familial cases (71.4%) and 14 sporadic cases (28.6%). Two of these mutations (c.649dupC, c.620_621delAA) had already been reported, while other 2 (c.1018_1019delAA, c.1012+1G>A) were previously undocumented. The tumor necrosis factor (TNF)-α level in the PKD group was significantly higher than that in the age- and sex-matched control group (P=0.025). There were no significant differences in the interleukin (IL)-1ß, IL-2R, IL-6, IL-8, or IL-10 levels between the two groups. CONCLUSION: In this study, we summarized the clinical and genetic characteristics of PKD. We found that the serum TNF-α levels were elevated in patients clinically diagnosed with PKD, suggesting that an inflammatory response is involved in the pathogenesis of PKD.

IFP35 as a promising biomarker and therapeutic target for the syndromes induced by SARS-CoV-2 or influenza virus.

Previous studies have shown that the high mortality caused by viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus primarily results from complications of a cytokine storm. Therefore, it is critical to identify the key factors participating in the cytokine storm. Here we demonstrate that interferon-induced protein 35 (IFP35) plays an important role in the cytokine storm induced by SARS-CoV-2 and influenza virus infection. We find that the levels of serum IFP35 in individuals with SARS-CoV-2 correlates with severity of the syndrome. Using mouse model and cell assays, we show that IFP35 is released by lung epithelial cells and macrophages after SARS-CoV-2 or influenza virus infection. In addition, we show that administration of neutralizing antibodies against IFP35 considerably reduces lung injury and, thus, the mortality rate of mice exposed to viral infection. Our findings suggest that IFP35 serves as a biomarker and as a therapeutic target in virus-induced syndromes.

The dynamics of immune response in COVID-19 patients with different illness severity.

This study aimed to analyze the dynamic changes of lymphocyte subsets and specific antibodies in coronavirus disease 2019 (COVID-19) patients with different illness severity. The amounts of lymphocyte subsets and the levels of immunoglobulin M (IgM) and IgG antibody were retrospectively analyzed in 707 COVID-19 cases. The amounts of lymphocyte subsets were significantly decreased with the increased severity of illness and the levels of IgM and IgG were lower in critical cases than severe and moderate cases. In deceased patients, the lymphocytes subsets were significantly lower than recovered patients. However, the relationship between the levels of IgM and IgG and the amounts of lymphocyte subsets were not significantly correlated. During different stages of COVID-19, the total T cell, CD4+ T cell, and CD8+ T cell counts were gradually recovered to the normal levels in severe and critical groups but the changing trend was relatively stable in the moderate group. The production of IgM and IgG antibodies were delayed in critical groups but also could reach the peak levels at one month after illness onset and decreased to background levels. To detect the kinetics of lymphocytes and antibodies has important clinical value in predicting the illness severity and understanding the pathogenesis of COVID-19.

Longitudinal Profile of Laboratory Parameters and Their Application in the Prediction for Fatal Outcome Among Patients Infected With SARS-CoV-2: A Retrospective Cohort Study.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) experience a wide clinical spectrum, with over 2% developing fatal outcome. The prognostic factors for fatal outcome remain sparsely investigated. METHODS: A retrospective cohort study was performed in a cohort of patients with confirmed COVID-19 in one designated hospital in Wuhan, China, from 17 January-5 March 2020. The laboratory parameters and a panel of cytokines were consecutively evaluated until patients' discharge or death. The laboratory features that could be used to predict fatal outcome were identified. RESULTS: Consecutively collected data on 55 laboratory parameters and cytokines from 642 patients with COVID-19 were profiled along the entire disease course, based on which 3 clinical stages (acute stage, days 1-9; critical stage, days 10-15; and convalescence stage, day 15 to observation end) were determined. Laboratory findings based on 75 deceased and 357 discharged patients revealed that, at the acute stage, fatality could be predicted by older age and abnormal lactate dehydrogenase (LDH), urea, lymphocyte count, and procalcitonin (PCT) level. At the critical stage, the fatal outcome could be predicted by age and abnormal PCT, LDH, cholinesterase, lymphocyte count, and monocyte percentage. Interleukin 6 (IL-6) was remarkably elevated, with fatal cases having a more robust production than discharged cases across the whole observation period. LDH, PCT, lymphocytes, and IL-6 were considered highly important prognostic factors for COVID-19-related death. CONCLUSIONS: The identification of predictors that were routinely tested might allow early identification of patients at high risk of death for early aggressive intervention.

Precautionary Measures: Performing ERCP on a Patient With Juxtapapillary Duodenal Diverticula (JPDD)-Related Biliary Stone After COVID-19 Lockdown Restriction Lifted in Wuhan, China.

On April 8, 2020, after nearly 3 months of battling against the outbreak of COVID-19, Wuhan, where the pandemic began, began easing lockdown restrictions. However, given that asymptomatic carriers could continue to lead to transmission of COVID-19 during the very early stages, the endoscopists have taken precautions and conduct risk assessments to perform endoscopic intervention in this transition stage. Here, we have reported an urgent ERCP in a patient with acute pancreatitis secondary to JPDD-related biliary stone. Based on our experiences, the objective is to provide practical suggestions for the safe resumption of ERCP procedures in the setting of the COVID-19 pandemic with specific focus on patient risk assessment, personal protection equipment (PPE), and dress code modalities, all of which have been implemented in our hospital to reduce the risk of viral transmission.

Clinical characteristics of confirmed and clinically diagnosed patients with 2019 novel coronavirus pneumonia: a single-center, retrospective, case-control study.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. At the peak of the outbreak in Wuhan (January and February), there are two types of COVID-19 patients: laboratory confirmation and clinical diagnosis. This study aims to compare and analyze the clinical outcomes and characteristics of confirmed and clinically diagnosed COVID-19 patients to determine whether they are of the same type and require equal treatment. More importantly, the prognostic factors of COVID-19 patients are explored. METHODS: A total of 194 hospitalized patients with COVID-19 pneumonia were retrospectively studied. Demographic data, clinical characteristcs, laboratory results and prognostic information were collected by electronic medical record system and analyzed. RESULTS: Among 194 subjects included, 173 were confirmed and 21 were clinically diagnosed. There were no significant differences in clinical outcomes (mortality rate 39[22.54%] vs 7[33.33%], P=0.272) and hospital stay (19.00 vs 16.90 days, P=0.411) between the confirmed and clinically diagnosed group, and prognostic factors were similar between them. Older age, lower albumin levels, higher serum Lactate dehydrogenase (LDH) levels, higher D-D levels, longer prothrombin time (PT), higher IL-6 levels, lower T cells indicated poor prognosis in patients with COVID-19 pneumonia. NK cell has the highest AUC among all measured indicators (NK AUC=0.926, P<0.001). CONCLUSION: Laboratory-confirmed and clinically diagnosed COVID-19 patients are similar in clinical outcomes and most clinical characteristics. They are of the same type and require equal treatment. Age, AST, LDH, BUN, PT, D-D, IL6, white blood cell and neutrophil counts, T cell and T cell subset counts can efficiently predict clinical outcomes.

Serum levels of retinol-binding protein 4 and the risk of non-small cell lung cancer: A case-control study.

Retinol binding protein 4 (RBP4), as an adipokine, has been identified to be associated with several types of cancer. However, no studies have assessed its effect on non-small cell lung cancer (NSCLC) risk. The objective of this study was to assess the association between serum RBP4 levels and the risk of NSCLC.A case-control study design was used to recruit 256 confirmed NSCLC cases and 256 age- and gender-matched healthy controls by frequency between August 2017 and January 2019. Serum RBP4 was measured using enzyme-linked immune absorbent assay before treatment. Unconditional logistic regression analysis was applied to estimate the odds ratio and 95% confidence interval (CI).Serum RBP4 level was significantly higher in NSCLC patients than those in the healthy control group (36.05 ±â€Š8.28 vs 29.54 ±â€Š7.71 µg/mL, P < .05). Higher serum RBP4 level was associated with increased risk of NSCLC (P trend = .001). Compare with those in the lowest tertile, the adjusted odds ratios were 1.85 (95% CIs 1.07-3.2) (P = .029) for the second tertile and 2.18 (95% CIs 1.37-3.45) (P = .001) for the highest tertile after adjusting for confounding variables. No interactions were observed after stratified analyses by body mass index and smoking status (P for interaction: .584 and .357).Our study indicated that serum RBP4 level was positively related to the risk of NSCLC. Additional studies with prospective design are required to confirm this finding.

Effectiveness of Arbidol for COVID-19 Prevention in Health Professionals.

Background: Frontline health professionals are a COVID-19-susceptible population during the outbreak of COVID-19, but prophylactic drugs against SARS-CoV-2 infection are to be explored. Method: Frontline health professionals diagnosed with COVID-19 before February 9, 2020 in Tongji Hospital, Wuhan, China and the same amount of controls in the uninfected group were included in this study. Clinical and laboratory data were collected with standardized forms. Results: A total of 164 subjects were included in this study, 82 cases in the infected group and 82 controls in the uninfected group, with a median age of 37 years, including 63 males and 101 females. Nineteen (23.2%) patients in the infected group were administered oral arbidol, and 48 (58.5%) in the uninfected group (OR = 0.214, 95% CI 0.109-0.420). The cumulative uninfected rate of health professionals in the arbidol group was significantly higher than that of individuals in the non-arbidol group (log-rank test, χ2 = 98.74; P < 0.001). Forty-eight patients (58.5%) in the infection group were hospitalized, with a median age of 39 (31-49) years, of whom 7 (14.6%) were prophylactically administered arbidol. Thirty-four patients (41.5%) with mild symptoms were treated outside the hospital, among which the median age was 34 (30-39) years, and twelve patients (35.3%) took prophylactic oral arbidol. The hospitalization rate was significantly associated with age (P = 0.024) and oral arbidol administration (OR = 0.313, 95% CI 0.108-0.909). In the age-matched case-control study, the hospitalization rate was not significantly associated with arbidol administration (P = 0.091). Conclusion: Prophylactic oral arbidol was associated with a lower incidence of SARS-CoV-2 infection but not hospitalization rate in health professionals, providing a basis for the selection of prophylactic drugs for high-risk populations.

Clinical characteristics of confirmed and clinically diagnosed patients with 2019 novel coronavirus pneumonia: a single-center, retrospective, case-control study.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. At the peak of the outbreak in Wuhan (January and February), there are two types of COVID-19 patients: laboratory confirmation and clinical diagnosis. This study aims to compare and analyze the clinical outcomes and characteristics of confirmed and clinically diagnosed COVID-19 patients to determine whether they are of the same type and require equal treatment. More importantly, the prognostic factors of COVID-19 patients are explored. METHODS: A total of 194 hospitalized patients with COVID-19 pneumonia were retrospectively studied. Demographic data, clinical characteristcs, laboratory results and prognostic information were collected by electronic medical record system and analyzed. RESULTS: Among 194 subjects included, 173 were confirmed and 21 were clinically diagnosed. There were no significant differences in clinical outcomes (mortality rate 39[22.54%] vs 7[33.33%], P = 0.272) and hospital stay (19.00 vs 16.90 days, P = 0.411) between the confirmed and clinically diagnosed group, and prognostic factors were similar between them. Older age, lower albumin levels, higher serum Lactate dehydrogenase (LDH) levels, higher D-D levels, longer prothrombin time (PT), higher IL-6 levels, lower T cells indicated poor prognosis in patients with COVID-19 pneumonia. NK cell has the highest AUC among all measured indicators (NK AUC = 0.926, P < 0.001). CONCLUSION: Laboratory-confirmed and clinically diagnosed COVID-19 patients are similar in clinical outcomes and most clinical characteristics. They are of the same type and require equal treatment. Age, AST, LDH, BUN, PT, D-D, IL6, white blood cell and neutrophil counts, T cell and T cell subset counts can efficiently predict clinical outcomes.

ANTECEDENTES: El nuevo coronavirus 2019 (COVID-19) es una nueva enfermedad infecciosa causada por el virus SARS-CoV-2. Durante el pico del brote en Wuhan (enero y febrero 2020), se detectaron dos tipos de pacientes portadores del COVID-19: pacientes confirmados a través de pruebas de laboratorio y pacientes confirmados por diagnóstico clínico. El objetivo de este estudio es comparar y analizar los resultados clínicos y las características de los pacientes con COVID-19 confirmados y clínicamente diagnosticados para determinar si son del mismo tipo y si necesitan el mismo tratamiento. El estudio es importante también para explorar los factores pronósticos de los pacientes con COVID-19. MÉTODOS: Un total de 194 pacientes hospitalizados con neumonía COVID-19 fueron estudiados retrospectivamente. Se utilizó un sistema de registro médico electrónico para recopilar los datos demográficos, las características clínicas, los resultados de laboratorio y la información pronóstica, para luego ser analizada. RESULTADOS: De los 194 pacientes incluidos, 173 dieron positivo y 21 fueron diagnosticados clínicamente. No se presentaron diferencias significativas en los resultados clínicos (tasa de mortalidad 39 [22,54%] vs. 7 [33,33%], p = 0,272) y la estancia hospitalaria (19,00 vs. 16,90 días, p = 0,411) entre el grupo de confirmados y el grupo diagnosticado clínicamente, y los factores pronósticos fueron similares entre ellos. Edad avanzada, niveles más bajos de albúmina, niveles más altos de lactato deshidrogenasa (LDH) en suero, niveles más altos de D-D, mayor tiempo de protrombina (PT), altos niveles de IL-6, células T más bajas indicaban mal pronóstico en pacientes con neumonía por COVID-19. La célula NK tiene el AUC más alto entre todos los indicadores medidos (NK AUC = 0,926, p < 0,001). CONCLUSIÓN: Los grupos de pacientes COVID-19 confirmados en laboratorio y diagnosticados clínicamente arrojan resultados clínicos similares y tienen la mayoría de las características clínicas. Son del mismo tipo y requieren el mismo tratamiento. La edad, AST, LDH, BUN, PT, D-D, IL6, los recuentos de glóbulos blancos y neutrófilos, recuentos de subgrupos de células T y células T pueden predecir los resultados clínicos de forma eficaz.