Identification and characterization of Necdin as a target for the Cockayne syndrome B protein in promoting neuronal differentiation and maintenance.

Cockayne syndrome (CS) is a devastating autosomal recessive genetic disorder, mainly characterized by photosensitivity, growth failure, neurological abnormalities, and premature aging. Mutations in CSB (ERCC6) are associated with almost all clinical phenotypes resembling classic CS. Using RNA-seq approach in multiple cell types, we identified Necdin (NDN) as a target of the CSB protein. Supportive of the RNA-seq results, CSB directly binds to NDN and manipulates the remodeling of active histone marks and DNA 5mC methylation on the regulatory elements of the NDN gene. Intriguingly, hyperactivation of NDN due to CSB deficiency does not interfere with nucleotide excision repair (1), but greatly affects neuronal cell differentiation. Inhibition of NDN can partially rescue the motor neuron defects in CSB mouse models. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for intervention, these data substantiate a reciprocal communication between CSB and NDN in the context of general transcription regulation.

Increased suicidal erythrocyte death in patients with hepatitis B-related acute-on-chronic liver failure.

Anemia is a common complication of hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Eryptosis, a suicidal erythrocyte death characterized by phosphatidylserine (PS) externalization and red blood cell-derived microparticle (RMP) generation, decreases erythrocyte lifespan. Herein, we investigated whether enhanced eryptosis is involved in the anemia pathophysiology associated with HB-ACLF. PS exposure, cell volume, cytosolic Ca2+, and reactive oxygen species (ROS) production were determined using flow cytometry. RMPs were extracted using a polyethylene glycol (PEG)-based method. We found that hemoglobin (Hb) and hematocrit (Hct) were significantly lower in patients with HB-ACLF than in healthy controls (HC), patients with chronic hepatitis B (CHB), and patients with cirrhosis. The direct antiglobulin test positive rate was 75.9% in patients with HB-ACLF while its intensity was associated with anemia. The ratio of abnormal erythrocytes was higher in patients with HB-ACLF than in HC, CHB, and cirrhosis. The percentage of PS-exposed erythrocytes was higher in patients with HB-ACLF (2.07 ± 0.11%) compared with HC (0.37 ± 0.05%), CHB (0.38 ± 0.03%), and cirrhosis (0.38 ± 0.04%). The cytosolic Ca2+ and ROS abundance were also higher in patients with HB-ACLF compared with HC, patients with CHB, and patients with cirrhosis, and were inversely correlated with the anemia in patients with HB-ACLF. PS exposure of erythrocytes collected from HC was significantly pronounced following incubation in plasma from patients with HB-ACLF compared with incubation in plasma from HC. The protein concentration and RMPs size significantly increased in patients with HB-ACLF compared with HC. Thus, the anemia in patients with HB-ACLF is associated with increased eryptosis, which is partially triggered by increased cytosolic Ca2+ and oxidative stress.NEW & NOTEWORTHY Acute chronic liver failure (ACLF) is a critical syndrome characterized by multiple organ failures and high short-term mortality. A common complication of HB-ACLF is anemia, however, the mechanism of anemia in HB-ACLF remains to be elucidated. We confirm that the accelerated eryptosis is involved in the pathophysiology of anemia associated with HB-ACLF, which progressively aggravates the clinical outcome. Our study illustrates the mechanism regarding the anemia pathogenesis of HB-ACLF, which may be utilized further toward therapeutic ends.

Development and implementation of an LIS-based validation system for autoverification toward zero defects in the automated reporting of laboratory test results.

BACKGROUND: Validation of the autoverification function is one of the critical steps to confirm its effectiveness before use. It is crucial to verify whether the programmed algorithm follows the expected logic and produces the expected results. This process has always relied on the assessment of human-machine consistency and is mostly a manually recorded and time-consuming activity with inherent subjectivity and arbitrariness that cannot guarantee a comprehensive, timely and continuous effectiveness evaluation of the autoverification function. To overcome these inherent limitations, we independently developed and implemented a laboratory information system (LIS)-based validation system for autoverification. METHODS: We developed a correctness verification and integrity validation method (hereinafter referred to as the "new method") in the form of a human-machine dialog. The system records personnel review steps and determines whether the human-machine review results are consistent. Laboratory personnel then analyze the reasons for any inconsistency according to system prompts, add to or modify rules, reverify, and finally improve the accuracy of autoverification. RESULTS: The validation system was successfully established and implemented. For a dataset consisting of 833 rules for 30 assays, 782 rules (93.87%) were successfully verified in the correctness verification phase, and 51 rules were deleted due to execution errors. In the integrity validation phase, 24 projects were easily verified, while the other 6 projects still required the additional rules or changes to the rule settings. Taking the Hepatitis B virus test as an example, from the setting of 65 rules to the automated releasing of 3000 reports, the validation time was reduced from 452 (manual verification) to 275 h (new method), a reduction in validation time of 177 h. Furthermore, 94.6% (168/182) of laboratory users believed the new method greatly reduced the workload, effectively controlled the report risk and felt satisfied. Since 2019, over 3.5 million reports have been automatically reviewed and issued without a single clinical complaint. CONCLUSION: To the best of our knowledge, this is the first report to realize autoverification validation as a human-machine interaction. The new method effectively controls the risks of autoverification, shortens time consumption, and improves the efficiency of laboratory verification.

Prevalence of hepatitis B virus, hepatitis C virus, human immunodeficiency virus and Treponema pallidum infections in hospitalized patients before transfusion in Xiangya hospital Central South University, China from 2011 to 2016.

BACKGROUND: Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Treponema pallidum (TP) infections are considered classic transfusion-transmissible infections (TTIs). Few data are available about the prevalence of TTIs in patients before blood transfusion in China. This study aimed to investigate the seroprevalence of four TTIs among patients before blood transfusion in Xiangya Hospital Central South University, China. METHODS: From 2011 to 2016, 442,121 hospitalized patients before possible blood transfusion were tested for hepatitis B surface antigen (HBsAg), anti-HCV, syphilis antibody (anti-TP) and anti-HIV. RESULTS: Of the 442,121 patients, the overall positivity of the four TTI serum markers was 15.35%. The positive rates of HBsAg, anti-HCV, anti-HIV and anti-TP were 10.98, 1.43, 0.16 and 2.78%, respectively. TTI serum markers showed a significant difference by gender, with positive rates of 17.98% for males and 12.79% for females. The prevalence of TTI serum markers varied significantly by age. The overall co-infection rate was 0.63%, and the top three multiple infections were HBV-TP, HBV-HCV, and HCV-TP. The co-infection rates of HBV-TP and HBV-HCV showed a significant decrease from 2011 to 2016, while the rates of other co-infections remained stable. CONCLUSIONS: The prevalence of TTIs in patients before blood transfusion is much higher compared to that in blood donors in the region. The infection rates of HIV and TP increased, and the infection rate of HBsAg decreased in recent years.

Retrospective analysis of 30 severe autoimmune hemolytic anemia patients treated by whole blood exchange transfusion.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) results from the excessive destruction of red blood cells (RBCs). Nowadays, there is no exact treatment for severe AIHA and our current medical therapies do not effectively stop the progression of severe AIHA. Therapeutic plasma exchange (TPE) is used as emergency therapy that is sometimes helpful. Whole blood exchange (WBE) is based on TPE while its replacement liquids are donor RBCs and fresh plasma. We hypothesized that WBE transfusion might be able to control the process of acute hemolysis, avoid the hemolytic crisis, and improve severe hemolytic anemic symptoms rapidly. The objective was to investigate the efficiency of WBE on severe AIHA. STUDY DESIGN AND METHODS: Thirty severe AIHA patients were treated with WBE in our hospital from June 2003 to August 2013. An apheresis instrument (COBE Spectra, TerumoBCT) was employed in WBE procedure. We retrospectively analyzed the results of these severe anemic patients. RESULTS: Twelve hours after WBE treatment, 26 of 30 (86.7%) patients' Hb levels were elevated immediately. Their total bilirubin concentration, direct bilirubin levels, and titers of antibodies were decreased, and clinical symptoms were relieved rapidly. Two (6.7%) patients' hemolysis was stopped from deteriorating, one (3.3%) patient's hemolysis was not controlled by the treatment due to malignancy, and another (3.3%) patient died from pleural hemorrhage of Evans syndrome. CONCLUSION: This study suggests that WBE is an effective therapy for severe AIHA. Further investigation of this application is warranted.

Lymphoplasmapheresis versus plasma exchange in severe myasthenia gravis: a retrospective cohort study.

Background: Lymphoplasmapheresis (LPE) is a new therapy developed on the basis of traditional plasma exchange (PE) in combination with leukapheresis. Currently, it remains unclear whether PE and LPE show differences in efficacy for severe MG. Methods: A retrospective analysis was conducted on 198 MG patients, 75 in the PE group and 123 in the LPE group, and the patients' Myasthenia Gravis Foundation of America (MGFA) Clinical Classification was Class IV. The treatment outcome was the change in Quantitative Myasthenia Gravis Score (QMGS) from baseline to the end of treatment. Propensity score matching (PSM) was applied for the balance of confounders between the two groups. Results: In this study cohort, the safety profile of LPE and PE was good and no serious adverse events were observed. Based on PSM, 62 patients treated with LPE and 62 patients treated with PE were entered into a comparative efficacy analysis. In the PE group, patients underwent a total of 232 replacements, with a mean of 3.74. PE significantly improved the patients' QMGS performance, with the mean QMGS decreasing from 22.98 ± 4.03 points at baseline to 18.34 ± 5.03 points after treatment, a decrease of 4.68 ± 4.04 points (p < 0.001). A decrease of ≥3 points in QMGS was considered a significant improvement, with a treatment response rate of 67.7% in the PE group. In the LPE group, patients received a total of 117 replacements, with a mean of 1.89. The patients' mean QMGS was 23.19 ± 4.11 points at baseline and was 16.94 ± 5.78 points after treatment, a decrease of 6.26 ± 4.39 points (p < 0.001). The improvement in QMGS was more significant in patients treated with LPE compared to the PE group (p = 0.039). The treatment response rate in the LPE group was 79%, which was not significantly different compared to the PE group (p = 0.16). The LEP group had a shorter mean length of stay compared to the PE group (10.86 ± 3.96 vs. 12.14 ± 4.14 days), but the difference was not statistically significant (p = 0.13). During the 2-month follow-up period, LPE may be associated with better functional outcomes for patients, with lower QMG score and relapse rate. LPE and PE were both effective in reducing the levels of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and AChR-Ab. Compared to PE, LPE was superior in the reduction of AChR-Ab titer. Conclusion: In severe MG, LPE may be a more preferred treatment option than PE. It achieves treatment outcomes that are not inferior to or even better than PE with fewer replacements. This study provides further evidence to support the application of LPE as a new treatment option for MG.

Effectiveness of lymphoplasmapheresis compared with therapeutic plasma exchange for thrombotic thrombocytopenic purpura: a retrospective evaluation.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening disease usually treated with therapeutic plasma exchange (TPE), but some patients are refractory to TPE. The study aimed to compare lymphoplasmapheresis (LPE), an innovative treatment for TTP based on plasma exchange, with TPE in TTP treatment. METHODS: This retrospective study included patients with TTP treated at Xiang-Ya Hospital in China during 2009-2018. All patients with microangiopathic hemolysis and thrombocytopenia who received either LPE or TPE were included. The treatment outcomes were the number of sessions, volume of plasma, time in hospital, hospital costs, and rates of remission and relapse. All patients attended the hospital for follow-up. RESULTS: Forty-five patients were included in the study; 18 received TPE and 27 LPE. There were no significant differences in sex, etiology of TTP, initial platelet count, schistocyte, LDH, and bilirubin between the two groups. At the time of discharge, patients treated with TPE required more treatment sessions (4.5 vs. 2, P=0.04) and higher plasma volume (7300 vs. 3100 ml, P=0.01) than patients treated with LPE. The proportions of remission (P=0.197) and relapse (P=0.257) were not significantly different between the two groups. The time to remission from admission (P=0.75) and the time to remission from first therapy (P=0.53) were also not significantly different between the two groups. CONCLUSION: Compared with TPE, LPE reduced the number of treatment sessions and plasma volume needed to treat TTP. Therefore, we propose that LPE might be a suitable treatment for TTP.

Lymphoplasma Exchange Improves Myasthenia Gravis Exacerbations: A Retrospective Study in a Chinese Center.

Background: Lymphoplasma exchange (LPE), a technique combining plasma exchange with leukapheresis, is emerging as promising treatment for autoimmune diseases. Data on the efficacy and safety of LPE in myasthenia gravis (MG) therapy are scarce. In this study, we aimed to comprehensively review the clinical efficacy, safety, and immunological characteristics of LPE therapy in MG patients. Study Design and Methods: A Chinese cohort of 276 generalized MG patients in state of exacerbation, including impeding crisis, myasthenia crisis, and preparation for thoracic exsection between January 2014 and December 2020, were evaluated in this study. Results: A total of 276 patients with a median age of 45.5 ± 16.7 years underwent a total of 635 LPE sessions. Clinical scales of Quantitative Myasthenia Gravis (QMG) scores, Myasthenia Gravis Specific Manual Muscle Testing (MMT) scores, activities of daily living (ADL) scores, and quality of life (QOL) scores were improved during 4 weeks' follow-up. Adverse effects occurred in 20 out of 276 patients, with 14 patients having one adverse event each. Independent predictive factors for good response to LPE therapy were symptom onset before LPE therapy ≤3 days and age on LPE therapy <50 years of age. LPE decreased the serum levels of antibodies, immunoglobulins, and complements 4 weeks after the first replacement, with decreased levels of interleukin (IL)-17A and interferon (IFN)-γ and increased level of IL-10. Conclusion: LPE is an effective treatment for MG patients in state of exacerbation and preparation for thymectomy. Early use of LPE on early-onset MG may have good therapeutic effects. The potential mechanism for LPE is the polarization of cytokines from IL-17A, IFN-γ, into IL-10.

Application of lymphoplasmapheresis in the treatment of severe myasthenia gravis.

Background: Lymphoplasmapheresis (LPE) is a treatment that combines traditional plasma exchange and lymphocyte removal technique. It has been applied to treat a variety of autoimmune diseases, but its application value in the treatment of severe myasthenia gravis (MG) is not yet clear. Therefore, the aim of this study was to investigate the efficacy and safety of LPE in severe MG. Methods: Clinical data of 123 severe patients with MG (Myasthenia Gravis Foundation of America Clinical Classification, Class IV) who received LPE treatment were included in a retrospective analysis. Efficacy was evaluated by the change of Quantitative Myasthenia Gravis score (QMGS) before and after treatment. Univariate and multivariate logistic regression analysis was used to explore clinical factors affecting efficacy. Results: A total of 220 replacements were performed in 123 patients, with an average of 1.79 replacements per patient. The overall safety of LPE was good, and no serious adverse reactions occurred. After treatment, the mean QMGS of patients decreased significantly, from 23.40 ± 4.25 points before treatment to 17.93 ± 5.61 points after treatment, a decrease of 5.47 ± 4.16 points. 75.6% of patients experienced remission of clinical symptoms. During a 2-month follow-up of 64 patients, a progressive improvement in QMGS was found. Each muscle group involved in MG responded well to LPE treatment. In addition, LPE significantly reduced the levels of AChR-Ab and inflammatory cytokines in patients. Age ≥ 50 years and co-infection were unfavorable factors affecting the efficacy. Conclusions: In this study cohort, LPE is safe for the treatment of severe MG and achieves good treatment outcome with fewer replacements. In patients with MG, the avoidance and timely control of infection are necessary. Our study provides a potential new treatment option for severe MG.

Convalescent plasma to treat COVID-19: clinical experience and efficacy.

The recent outbreak of COVID-19 in the world is currently a big threat to global health and economy. Convalescent plasma has been confirmed effective against the novel corona virus in preliminary studies. In this paper, we first described the therapeutic schedule, antibody detection method, indications, contraindications of the convalescent plasmas and reported the effectiveness of convalescent plasma therapy by a retrospective cohort study.

Exchange transfusion of least incompatible blood for severe hemolytic disease of the newborn due to anti-Rh17.

HDN attributed to the rare Rh variants has become more and more significant caused by anti-D, but the compatible blood is usually very difficult to obtain when exchange transfusion is required. We treated a 10-hour neonate of O, D + C + c - E - e+ blood group with severe HDN due to anti-Rh17 with least incompatible blood typed O, D + C - c + E + e-. The neonatal hemolysis was relieved obviously and bilirubin was reduced gradually after exchange transfusion. The infant was discharged in good health 13 days after birth with 135.0 g/L, 28.0 micromol/L and 10.7 micromol/L of Hb, total bilirubin and direct bilirubin, respectively. No sequelae were observed in a three-year follow-up. The result suggesting that the least incompatible blood is an alternative choice for exchange transfusion in severe HDN due to anti-Rh17 in case that Rh17 antigen-negative blood is unavailable.

Integrative Analysis of Sirtuins and Their Prognostic Significance in Clear Cell Renal Cell Carcinoma.

Sirtuins, class III histone deacetylases, are involved in multiple biological processes in cancer initiation and progression. However, the diverse expression patterns and prognostic values of sirtuins in cancers have yet to be elucidated. In this study, we first evaluated the expression and prognostic values of sirtuins in multiple cancer cohorts using publicly available TCGA pan-cancer datasets. Pan-cancer survival analysis indicated that 6 out of 7 sirtuin family members were significant associated with prognosis of clear cell renal cell carcinoma (KIRC) patients. SIRT1, SIRT3, SIRT4, and SIRT5 were associated with favorable prognosis of KIRC patients, while SIRT6 and SIRT7 were associated with unfavorable prognosis. The expression levels of SIRT4 and SIRT5 in KIRC tissues were lower than that in normal tissues, while SIRT6 and SIRT7 were higher in KIRC tissues. The expression levels of SIRT1, SIRT3, SIRT5, SIRT6, and SIRT7 were significantly correlated with tumor stage and histological grade. DNA methylation may contribute to the dysregulation of sirtuins. Finally, GSEA was conducted to predict the potential functions of sirtuins in KIRC. Our results may provide novel insights for the development of sirtuins-based cancer therapy in KIRC.

Low platelet count is a risk factor of postoperative pneumonia in patients with type A acute aortic dissection.

BACKGROUND: Previous studies have already established that low platelet count is related to adverse outcomes in patients with type A acute aortic dissection (AAAD). However, there are yet limited studies investigating the association of platelet count and the risk of postoperative pneumonia in AAAD patients. METHODS: This retrospective cohort study was conducted in Xiangya Hospital of Central South University from January 2014 to May 2019. Clinical and laboratory data were collected. The correlation between platelet count and postoperative pneumonia was analyzed using multivariate logistic regression and the area under the receiver operating characteristic curve (AUC) was used to assess the predictive power of platelet count on pneumonia. RESULTS: A total of 268 patients with AAAD were enrolled. The overall incidence of pneumonia was 36.94% (n=99). Multivariate logistic regression revealed that platelet count was negatively associated with the risk of postoperative pneumonia (OR 0.93; 95% CI: 0.88-0.98) after adjusting for the confounders. Compared to the lowest platelet count tertile (T1), medium platelet count (T2) and highest platelet count (T3) had a lower risk of postoperative pneumonia after adjusting for the confounders (OR 0.80, 95% CI: 0.40-1.60; OR 0.30, 95% CI: 0.13-0.66; respectively). A similar trend was observed when the platelet count was handled as categorical variables (tertiles). The area under the ROC curve was 0.635 (95% CI: 0.565-0.707), with a sensitivity of 76.77%, a specificity of 50.89% and an accuracy of 60.45%. CONCLUSIONS: Our findings indicate that low platelet count is an independent risk factor of postoperative pneumonia in patients with AAAD and has a specific predictive power on the risk of postoperative pneumonia.

[Clinical significance of anti-D IgG screening and titer detection in 286 RhD negative pregnant women].

OBJECTIVE: Anti-D IgG in RhD negative pregnant women is the main antibody of Rh-induced hemolytic disease of newborn (HDN). The study aimed to investigate the clinical significance of anti-D IgG screening and titer detection in RhD negative pregnant women. METHODS: Sera of 286 RhD negative pregnant women were collected. Microtube column indirect antiglobulin test was used to screen and identify anti-D IgG. The indirect antiglobulin test was used to test the titer of anti-D IgG. RESULTS: Anti-D IgG was identified in 21 cases (7.3%). The titer of anti-D showed an increasing trend with pregnancy progresses. The clinical outcomes of 12 fetuses (newborns) from positive anti-D pregnant women were observed. Two cases died in utero, 2 cases did not show abnormality and 8 cases had hemolysis. The 8 cases with hemolysis were treated with exchange transfusion or blood transfusion, and they had a good prognosis. CONCLUSIONS: The screening and titer detection of anti-D IgG in RhD negative pregnant women are valuable in the prediction and treatment of HDN.

[Lymphoplasmapheresis for Guillain-Barre syndrome].

OBJECTIVE: To evaluate the clinical therapeutic effect and security of lymphoplasmapheresis (LPE) for Guillain-Barre syndrome (GBS). METHODS: Sixty-six GBS patients were randomly divided into 2 groups: the therapy group (33 patients) were treated with LPE in addition to the medical treatment; the control group (33 patients) only accepted the medical treatment. The therapeutic effect was evaluated with the initial recovery time of myodynamia and the myodynamia score difference, and the side effect of the therapy group was observed. RESULTS: The therapy group were treated with LPE for 48 times,1.5 times per person. The average initial recovery time was quicker in the therapy group compared with that in the control group [(6.45+/-3.01) vs (8.36+/-3.83) days]. The difference of limb myodynamia score between pre-treatment and post-treatment in the therapy group was more than that in the control group. The improved number in the therapy group was more than that in the control group, but the ineffective number in the therapy group was not as many as that in the control group. The total effective rate in the therapy group was higher than that in the control group (51.5% vs 27.7%); the average hospital day in the therapy group was shorter than that in the control group [(19.42+/-7.25) vs (24.00+/-8.64) days]; and the difference had statistical significance(P<0.05). The average myodynamia score after the first LPE increased, but the difference had no statistical significance (P>0.05). After the second and the third LPE, the average myodynamia score continued to rise, and the difference had statistical significance (P<0.05). The incidence rate of side effects in the therapy group was 12.5%. Urticaria and hypotension were the major side effects, but they were light and could be relieved by symptomatic treatment. CONCLUSION: The therapeutic effect of LPE is definite, and the side effect is scarce. LPE is safe and effective, and it is worth of generalization and applying in clinical practice.

Retrospective analysis of 55 twin neonates with haemolytic disease of the newborn.

Haemolytic disease is a condition characterized by anaemia and jaundice, and the course may be more complicated in twins. We investigated the demographic and laboratory characteristics of twins with haemolytic disease of the newborn (HDN) and compared these characteristics between groups categorized according to multiple birth status (twins vs. singletons) and conception method (assisted reproductive technology (ART) vs. spontaneous conception). Fifty-five twins with HDN and 253 singletons with HDN who were born during the same period (controls) were included in the study, and we performed comparisons between them. The results showed that twin infants were more likely to be premature, have a low birth weight and be conceived via ART than their singleton counterparts. Moreover, a variety of comorbidities were identified more frequently in twins with HDN than singletons with HDN. The minimum haemoglobin and the initial and maximum total bilirubin, albumin and complement 3 (C3) were all significantly lower in twins than in singletons; however, these two groups were not found to differ significantly by direct antiglobulin test (DAT) status. Twins conceived via ART had a lower minimum haemoglobin and initial bilirubin than twins conceived spontaneously. The results of this study suggested that neonatal comorbidities were more common in twins with HDN than singletons with HDN; however, DAT positivity did not appear to play a major role in the higher rates of comorbidities and lower concentration of haemoglobin observed in twins. Among twins with HDN, conception via ART may serve as a risk factor for increased disease severity.