Analysis of related factors for neuropsychiatric comorbidities in children with epilepsy.

OBJECTIVE: To analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy. METHOD: We randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis. RESULTS: There were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P < 0.05), while there were no statistically significant differences in age, gender, age of onset, form of onset, interictal epileptiform discharge, history of febrile convulsion, and the time from onset to initial visit (P > 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability. CONCLUSION: The course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.

The prevalence rate, mortality, and 5-year overall survival of Schistosoma japonicum patients with human malignancy.

Background: Only a few studies have focused on the association between Schistosoma japonicum and human malignancy. The aim of this study was to update the prevalence rate, mortality, and 5-year overall survival of S. japonicum patients with human malignancy. Methods: From January 20, 2018, to January 31, 2021, 5,866 inpatients were included in the study. A total of 656 S. japonicum patients with malignancy were identified. Cases were stratified by gender and age groups. The cancer sites, prevalence rate, mortality, and 5-year overall survival of the patients were reported. The S. japonicum patients with malignancy were further divided into a non-digestive system tumor group (n = 309) and a digestive system tumor group (n = 347), including those with cancer in the esophagus, stomach, colon, rectum, liver, gallbladder, bile duct, or pancreas. Chi-squared test and odds ratio with confidence intervals were performed between these two groups. Results: Lung cancer was found the most common malignancy, accounting for 18.6% of all malignancies, followed by colorectal, stomach, liver, and gallbladder cancers. These five leading malignancies accounted for approximately 61.8% of all cases. Colorectal cancer was the leading cause of malignancy death, followed by lung, stomach, gallbladder, and liver cancers. These five leading causes of death accounted for approximately 55.6% of all death cases. Statistical significance was found in the prevalence rate between S. japonicum and non-S. japonicum patients with/without digestive system tumor (p < 0.001). The odds ratio of S. japonicum patients with digestive system tumors was 1.6 (95%CI: 1.4-1.9). Conclusion: S. japonicum contributes to a significant prevalence and mortality in digestive system tumors, including colorectal, stomach, liver, and gallbladder cancers.

Direct prediction of carbapenem resistance in Pseudomonas aeruginosa by whole genome sequencing and metagenomic sequencing.

Carbapenem resistance is a major concern in the management of antibiotic-resistant Pseudomonas aeruginosa infections. The direct prediction of carbapenem-resistant phenotype from genotype in P. aeruginosa isolates and clinical samples would promote timely antibiotic therapy. The complex carbapenem resistance mechanism and the high prevalence of variant-driven carbapenem resistance in P. aeruginosa make it challenging to predict the carbapenem-resistant phenotype through the genotype. In this study, using whole genome sequencing (WGS) data of 1,622 P. aeruginosa isolates followed by machine learning, we screened 16 and 31 key gene features associated with imipenem (IPM) and meropenem (MEM) resistance in P. aeruginosa, including oprD(HIGH), and constructed the resistance prediction models. The areas under the curves of the IPM and MEM resistance prediction models were 0.906 and 0.925, respectively. For the direct prediction of carbapenem resistance in P. aeruginosa from clinical samples by the key gene features selected and prediction models constructed, 72 P. aeruginosa-positive sputum samples were collected and sequenced by metagenomic sequencing (MGS) based on next-generation sequencing (NGS) or Oxford Nanopore Technology (ONT). The prediction applicability of MGS based on NGS outperformed that of MGS based on ONT. In 72 P. aeruginosa-positive sputum samples, 65.0% (26/40) of IPM-insensitive and 63.2% (24/38) of MEM-insensitive P. aeruginosa were directly predicted by NGS-based MGS with positive predictive values of 0.897 and 0.889, respectively. By the direct detection of the key gene features associated with carbapenem resistance of P. aeruginosa, the carbapenem resistance of P. aeruginosa could be directly predicted from cultured isolates by WGS or from clinical samples by NGS-based MGS, which could assist the timely treatment and surveillance of carbapenem-resistant P. aeruginosa.

The interaction of ammonia and manganese in abnormal metabolism of minimal hepatic encephalopathy: A comparison metabolomics study.

This study was to investigate the effects of ammonia and manganese in the metabolism of minimal hepatic encephalopathy (MHE). A total of 32 Sprague-Dawley rats were divided into four subgroups: chronic hyperammonemia (CHA), chronic hypermanganese (CHM), MHE and control group (CON). 1H-NMR-based metabolomics was used to detect the metabolic changes. Sparse projection to latent structures discriminant analysis was used for identifying and comparing the key metabolites. Significant elevated blood ammonia were shown in the CHA, CHM, and MHE rats. Significant elevated brain manganese (Mn) were shown in the CHM, and MHE rats, but not in the CHA rats. The concentrations of γ-amino butyric acid (GABA), lactate, alanine, glutamate, glutamine, threonine, and phosphocholine were significantly increased, and that of myo-inositol, taurine, leucine, isoleucine, arginine, and citrulline were significantly decreased in the MHE rats. Of all these 13 key metabolites, 10 of them were affected by ammonia (including lactate, alanine, glutamate, glutamine, myo-inositol, taurine, leucine, isoleucine, arginine, and citrulline) and 5 of them were affected by manganese (including GABA, lactate, myo-inositol, taurine, and leucine). Enrichment analysis indicated that abnormal metabolism of glutamine and TCA circle in MHE might be affected by the ammonia, and abnormal metabolism of GABA might be affected by the Mn, and abnormal metabolism of glycolysis and branched chain amino acids metabolism might be affected by both ammonia and Mn. Both ammonia and Mn play roles in the abnormal metabolism of MHE. Chronic hypermanganese could lead to elevated blood ammonia. However, chronic hyperammonemia could not lead to brain Mn deposition.

Ferrous sulfate reverses cerebral metabolic abnormality induced by minimal hepatic encephalopathy.

Orally administered ferrous iron was previously reported to significantly improve the cognition and locomotion of patients with minimal hepatic encephalopathy (MHE). However, the metabolic mechanisms of the therapeutic effect of ferrous iron are unknown. In this study, MHE was induced in rats by partial portal vein ligation (PPVL), and was treated with ferrous sulfate. The Morris water maze was used to evaluate the cognitive condition of the rats. The metabolites observed by NMR and validated by liquid chromatography-mass spectrometry were defined as the key affected metabolites. The enzyme activities and trace element contents in the rat brains were also investigated. The Mn content was found to be increased but the ferrous iron content decreased in the cortex and striatum in MHE. Decreased oxoglutarate dehydrogenase activity and increased glutamine synthetase (GS) and pyruvate carboxylase (PC) activity were observed in the cortex of MHE rats. Decreased pyruvate dehydrogenase activity and increased GS and PC activity were observed in the striatum of MHE rats. The levels of BCAAs and taurine were significantly decreased, and the contents of GABA, lactate, arginine, aspartate, carnosine, citrulline, cysteine, glutamate, glutamine, glycine, methionine, ornithine, proline, threonine and tyrosine were significantly increased. These metabolic abnormalities described above were restored after treatment with ferrous sulfate. Pathway enrichment analysis suggested that urea cycle, aspartate metabolism, arginine and proline metabolism, glycine and serine metabolism, and glutamate metabolism were the major metabolic abnormalities in MHE rats, but these processes could be restored and cognitive impairment could be improved by ferrous sulfate administration.

Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance.

It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

Magnetic resonance spectroscopy and liquid chromatography-mass spectrometry metabolomics study may differentiate pre-eclampsia from gestational hypertension.

OBJECTIVE: To investigate the findings of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and serum metabolomics for differentiating pre-eclampsia (PE) from gestational hypertension (GH). METHODS: This prospective study enrolled 176 subjects including a primary cohort with healthy non-pregnant women (HN, n = 35), healthy pregnant women (HP, n = 20), GH (n = 27), and PE (n = 39) and a validation cohort with HP (n = 22), GH (n = 22), and PE (n = 11). T1 signal intensity index (T1SI), apparent diffusion coefficient (ADC) value, and the metabolites on MRS were compared. The differentiating performances of single and combined MRI and MRS parameters for PE were evaluated. Serum liquid chromatography-mass spectrometry (LC-MS) metabolomics was investigated by sparse projection to latent structures discriminant analysis. RESULTS: Increased T1SI, lactate/creatine (Lac/Cr), and glutamine and glutamate (Glx)/Cr and decreased ADC value and myo-inositol (mI)/Cr in basal ganglia were found in PE patients. T1SI, ADC, Lac/Cr, Glx/Cr, and mI/Cr yielded an area under the curves (AUC) of 0.90, 0.80, 0.94, 0.96, and 0.94 in the primary cohort, and of 0.87, 0.81, 0.91, 0.84, and 0.83 in the validation cohort, respectively. A combination of Lac/Cr, Glx/Cr, and mI/Cr yielded the highest AUC of 0.98 in the primary cohort and 0.97 in the validation cohort. Serum metabolomics analysis showed 12 differential metabolites, which are involved in pyruvate metabolism, alanine metabolism, glycolysis, gluconeogenesis, and glutamate metabolism. CONCLUSIONS: MRS is expected to be a noninvasive and effective tool for monitoring GH patients to avoid the development of PE. KEY POINTS: • Increased T1SI and decreased ADC value in the basal ganglia were found in PE patients than in GH patients. • Increased Lac/Cr and Glx/Cr, and decreased mI/Cr in the basal ganglia were found in PE patients than in GH patients. • LC-MS metabolomics showed that the major differential metabolic pathways between PE and GH were pyruvate metabolism, alanine metabolism, glycolysis, gluconeogenesis, and glutamate metabolism.

Network Analysis and Nomogram in the Novel Classification and Prognosis Prediction of Advanced Schistosomiasis Japonica.

Clinical classification of advanced schistosomiasis japonica is important for treatment options and prognosis prediction. Network analysis was used to solve the problem of complexity and co-occurrence complications in classification of advanced schistosomiasis. A total of 4,125 retrospective patients were enrolled and divided randomly into a training cohort (n = 2,888) and a validation cohort (n = 1,237). Network analysis was used to cluster the isolated complications of advanced schistosomiasis. The accuracy of the network was evaluated. Nomograms based on the clustered complications were built to predict 1- to 5-year survival rates in advanced schistosomiasis. The predictive performance of the nomogram was also evaluated and validated. Fifteen isolated complications were identified: metabolic syndromes, minimal hepatic encephalopathy, hepatic encephalopathy, chronic obstructive pulmonary disease, pulmonary hypertension, respiratory failure, right heart failure, gastroesophageal variceal bleeding, gastrointestinal ulcer bleeding, splenomegaly, fibrosis, chronic kidney disease, ascites, colorectal polyp, and colorectal cancer. Through network analysis, three major clustered complications were achieved-namely, schistosomal abnormal metabolic syndromes (related to chronic metabolic abnormalities), schistosomal abnormal hemodynamics syndromes (related to severe portal hypertension and portosystemic shunting), and schistosomal inflammatory granulomatous syndromes (related to granulomatous inflammation). The nomograms showed a good performance in prognosis prediction of advanced schistosomiasis. The novel classification-based nomogram was useful in predicting the survival rate in advanced schistosomiasis japonica.

Oral magnesium sulphate administration in rats with minimal hepatic encephalopathy: NMR-based metabolic characterization of the brain

Objective: To investigate the metabolic changes in rats with minimal hepatic encephalopathy (MHE) treated with oral magnesium sulphate administration. Materials and Methods: A total of 30 Sprague-Dawley rats were divided into a control group and MHE group (further divided into an MHE group and an MHE-Mg group treated with oral administration of 124 mg/kg/day magnesium sulphate). Morris water maze (MWM), Y maze and narrow beam walking (NBW) were used to evaluate cognitive and motor functions. Brain manganese and magnesium content were measured. The metabolic changes in rats with MHE were investigated using hydrogen-nuclear magnetic resonance. Metabolomic signatures were identified with enrichment and pathway analysis. Results: A significantly decreased number of entries into the MWM within the range of interest, longer latency and total time during NBW, and higher brain manganese content were found in rats with MHE. After magnesium sulphate treatment, the rats with MHE had better behavioural performance and lower brain manganese content. The 25 and 26 metabolomic signatures were identified in the cortex and striatum of rats with MHE. The pathway analysis revealed alanine, aspartate and glutamate metabolism as the major abnormal metabolic pathways associated with these metabolomic signatures. Conclusion: Alanine, aspartate and glutamate metabolism are major abnormal metabolic pathways in rats with MHE, which could be restored by magnesium sulphate treatment.

Radiomics feature as a preoperative predictive of lymphovascular invasion in early-stage endometrial cancer: A multicenter study.

Background: The presence of lymphovascular space invasion (LVSI) has been demonstrated to be significantly associated with poor outcome in endometrial cancer (EC). No effective clinical tools could be used for the prediction of LVSI preoperatively in early-stage EC. A radiomics nomogram based on MRI was established to predict LVSI in patients with early-stage EC. Methods: This retrospective study included 339 consecutive patients with early-stage EC with or without LVSI from five centers. According to the ratio of 2:1, 226 and 113 patients were randomly assigned to a training group and a test group, respectively. Radiomics features were extracted from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), contrast-enhanced (CE), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps. The radiomics signatures were constructed by using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm in the training group. The radiomics nomogram was developed using multivariable logistic regression analysis by incorporating radiomics signatures and clinical risk factors. The sensitivity, specificity, and AUC of the radiomics signatures, clinical risk factors, and radiomics nomogram were also calculated. Results: The individualized prediction nomogram was constructed by incorporating the radiomics signatures with the clinical risk factors (age and cancer antigen 125). The radiomics nomogram exhibited a good performance in discriminating between negative and positive LVSI patients with AUC of 0.89 (95% CI: 0.83-0.95) in the training group and of 0.85 (95% CI: 0.75-0.94) in the test group. The decision curve analysis indicated that clinicians could be benefit from the using of radiomics nomogram to predict the presence of LVSI preoperatively. Conclusion: The radiomics nomogram could individually predict LVSI in early-stage EC patients. The nomogram could be conveniently used to facilitate the treatment decision for clinicians.

Prediction of pre-eclampsia by using radiomics nomogram from gestational hypertension patients.

Background: Pre-eclampsia (PE) is the main cause of death in maternal and prenatal morbidity. No effective clinical tools could be used for the prediction of PE. A radiomics nomogram based on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps was established to predict PE from gestational hypertension (GH). Materials and methods: A total of 138 patients with hypertensive disorders of pregnancy were continuously enrolled in the study prospectively, namely, 58 patients with PE and 80 patients with GH. The patients were randomly divided into a training cohort (n = 97) and a test cohort (n = 41). Radiomics features were extracted from DWI and ADC maps. The radiomics signature was constructed using a least absolute shrinkage and selection operator (LASSO) algorithm in the training cohort. A radiomics nomogram was developed by combining the radiomics signature with the selected clinical risk factors. The area under the receiver operating characteristic (ROC) curves (AUC), specificity, sensitivity, accuracy, positive predictive value, and negative predictive values of the radiomics signature, clinical risk factors, and radiomics nomogram were calculated. Decision curve analysis (DCA) was performed to determine the clinical usefulness of the radiomics nomogram. Results: The LASSO analysis finally included 11 radiomics features, which were defined as the radiomics signature. The individualized prediction nomogram was constructed by integrating the radiomics signature, maternal age, and body mass index (BMI). The nomogram exhibited a good performance both in the training cohort [AUC of 0.89 (95% CI, 0.82-0.95)] and test cohort [AUC of 0.85 (95% CI, 0.73-0.97)] for predicting PE from GH. The DCA indicated that clinicians and patients could benefit from the use of radiomics nomogram. Conclusion: The radiomics nomogram could individually predict PE from GH. The nomogram could be conveniently used to facilitate the treatment decision for clinicians and patients.

Radiomics Nomogram in Assisting Lymphadenectomy Decisions by Predicting Lymph Node Metastasis in Early-Stage Endometrial Cancer.

Background: Lymph node metastasis (LNM) is an important risk factor affecting treatment strategy and prognosis for endometrial cancer (EC) patients. A radiomics nomogram was established in assisting lymphadenectomy decisions preoperatively by predicting LNM status in early-stage EC patients. Methods: A total of 707 retrospective clinical early-stage EC patients were enrolled and randomly divided into a training cohort and a test cohort. Radiomics features were extracted from MR imaging. Three models were built, including a guideline-recommended clinical model (grade 1-2 endometrioid tumors by dilatation and curettage and less than 50% myometrial invasion on MRI without cervical infiltration), a radiomics model (selected radiomics features), and a radiomics nomogram model (combing the selected radiomics features, myometrial invasion on MRI, and cancer antigen 125). The predictive performance of the three models was assessed by the area under the receiver operating characteristic (ROC) curves (AUC). The clinical decision curves, net reclassification index (NRI), and total integrated discrimination index (IDI) based on the total included patients to assess the clinical benefit of the clinical model and the radiomics nomogram were calculated. Results: The predictive ability of the clinical model, the radiomics model, and the radiomics nomogram between LNM and non-LNM were 0.66 [95% CI: 0.55-0.77], 0.82 [95% CI: 0.74-0.90], and 0.85 [95% CI: 0.77-0.93] in the training cohort, and 0.67 [95% CI: 0.56-0.78], 0.81 [95% CI: 0.72-0.90], and 0.83 [95% CI: 0.74-0.92] in the test cohort, respectively. The decision curve analysis, NRI (1.06 [95% CI: 0.81-1.32]), and IDI (0.05 [95% CI: 0.03-0.07]) demonstrated the clinical usefulness of the radiomics nomogram. Conclusions: The predictive radiomics nomogram could be conveniently used for individualized prediction of LNM and assisting lymphadenectomy decisions in early-stage EC patients.

The Interaction of HLA-C1/KIR2DL2/L3 Promoted KIR2DL2/L3 Single-Positive/NKG2C-Positive Natural Killer Cell Reconstitution, Raising the Incidence of aGVHD after Hematopoietic Stem Cell Transplantation.

NKG2C+ natural killer (NK) cell plays a vital role in CMV infection control after hematopoietic stem cell transplantation (HSCT). However, the modulation on NKG2C+ NK cell reconstitution is still unclear. NK cell education is affected by the interactions of HLA-I/killer immunoglobulin receptor (KIR). Our aim is to figure out which HLA-I/KIR interaction plays a dominant role in NKG2C+ NK education. Based on allogeneic haploidentical HSCT, we investigated the expansion and function of single KIR positive NKG2C+ NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after HSCT. KIR2DL2/L3 single-positive/NKG2C+ cells were significantly expanded compared with KIR2DL1 or KIR3DL1 single-positive/NKG2C+ cells when donors and recipients were both HLA-C1/C1 or HLA-C1C1BW4 (p < 0.05), with higher NKp30 expression (p < 0.05). Moreover, the proportion of single KIR positive NK cells increased in both NKG2C+/NKG2A- NK cells and conventional NKG2C-/NKG2A- NK cells over time. We also observed that increased proportion of KIR2DL2/L3 single-positive/NKG2C+ NK cells correlated with higher incidence of acute graft-versus-host disease (aGVHD). Our study allows a better understanding of HLA-I/KIR interaction in the NKG2C+ NK cell education after HSCT.

Adoptive therapy with cytomegalovirus-specific T cells for cytomegalovirus infection after haploidentical stem cell transplantation and factors affecting efficacy.

Adoptive therapy with cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has emerged as an effective method for CMV infection. However, the efficacy reportedly ranges from 50% to 90%, and factors affecting anti-CMV efficacy have not been established. We investigated the safety and efficacy of adoptive therapy with CMV-CTLs for CMV infection in 190 patients after haploidentical stem cell transplantation (haplo-SCT), and importantly, we analyzed the main factors affecting antiviral efficacy. The CMV peak titer decreased from 19 (range, 1.0-503.0) × 103 copies/mL to 3.9 (range, 0-112) × 103 copies/mL after CMV-CTL infusion. The cumulative complete response (CR) rates in the first, fourth, and sixth weeks after the first CMV-CTL infusion were 37.9% (95% CI 35.0-40.8), 76.8% (95% CI 70.7-82.9), and 89.5% (95% CI 85.2-93.8), respectively. In multivariate analysis, persistent CMV infection prior to CMV-CTL infusion (hazard ratio [HR] 2.29, 95% CI 1.29-4.06, p = .005) and basiliximab treatment within 2 weeks of CMV-CTL infusion (HR 1.87, 95% CI 1.06-3.81, p = .031) were independent predictors of poor antiviral efficacy of CMV-CTL therapy. Our data showed that adoptive therapy with CMV-CTLs is a safe and effective treatment for CMV infection after haplo-SCT. Persistent CMV infection and basiliximab treatment are correlated with poor anti-CMV efficacy of CMV-CTL therapy.

Donor NKG2C homozygosity contributes to CMV clearance after haploidentical transplantation.

CMV infection remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several investigators have reported that adaptive NKG2C+ NK cells persistently expand during CMV reactivation. In our study, 2 cohorts were enrolled to explore the relationships among the NKG2C genotype, NKG2C+ NK cell reconstitution, and CMV infection. Multivariate analysis showed that donor NKG2C gene deletion was an independent prognostic factor for CMV reactivation and refractory CMV reactivation. Furthermore, adaptive NKG2C+ NK cells' quantitative and qualitative reconstitution, along with their anti-CMV function after transplantation, was significantly lower in patients grafted with NKG2Cwt/del donor cells than in those grafted with NKG2Cwt/wt donor cells. At day 30 after transplantation, quantitative reconstitution of NKG2C+ NK cells was significantly lower in patients with treatment-refractory CMV reactivation than in patients without CMV reactivation and those with nonrefractory CMV reactivation. In humanized CMV-infected mice, we found that, compared with those from NKG2Cwt/del donors, adaptive NKG2C+ NK cells from NKG2Cwt/wt donors induced earlier and stronger expansion of NKG2C+ NK cells as well as earlier and stronger CMV clearance in vivo. In conclusion, donor NKG2C homozygosity contributes to CMV clearance by promoting the quantitative and qualitative reconstruction of adaptive NKG2C+ NK cells after haploidentical allo-HSCT.

Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation.

Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8+ tetramer+ T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

Functional Competence of NK Cells via the KIR/MHC Class I Interaction Correlates with DNAM-1 Expression.

The interaction of inhibitory receptors with self-MHC class I (MHC-I) molecules is responsible for NK cell education. The intensity of DNAM-1 expression correlates with NK cell education. However, whether DNAM-1 expression directly influences the functional competence of NK cells via the KIR/MHC-I interaction remains unclear. Based on allogeneic haploidentical hematopoietic stem cell transplantation, we investigated the intensity of DNAM-1 expression on reconstituted NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after hematopoietic stem cell transplantation. The reconstituted NK cells educated by donor and recipient HLA molecules showed the highest DNAM-1 expression, whereas DNAM-1 expression on educated NK cells with only recipient HLA molecules was higher than that on educated NK cells with only donor HLA molecules, indicating that NK cells with donor or recipient HLA molecules regulate DNAM-1 expression and thereby affect NK cell education. Additionally, the effects of recipient cells on NK cell education were greater than those of donor cells. However, only when the DNAM-1, NKP30, and NKG2D receptors were blocked simultaneously was the function of educated and uneducated NK cells similar. Therefore, activating receptors may collaborate with DNAM-1 to induce educated NK cell hyperresponsiveness. Our data, based on in vitro and in vivo studies, demonstrate that the functional competence of NK cells via the KIR/MHC-I interaction correlates with DNAM-1 expression in human NK cells.

Some characteristics of clinical sequelae of COVID-19 survivors from Wuhan, China: A multi-center longitudinal study.

BACKGROUND: The pandemic of COVID-19 has a persistent impact on global health, yet its sequelae need to be addressed at a wide scale around the globe. This study aims to investigate the characteristics, prevalence, and risk factors for mid-term (>6 months) clinical sequelae in a cohort of COVID-19 survivors. METHODS: Totally 715 COVID-19 survivors discharged before April 1, 2020, from three medical centers in Wuhan, China, were included. The longitudinal study was conducted by telephone interviews based on a questionnaire including the clinical sequelae of general, respiratory, and cardiovascular systems. Demographics and some characteristics of clinical sequelae of the survivors were recorded and analyzed. Multivariate logistic regression analysis was applied to explore the risk factors for the sequelae. RESULTS: The median time interval from discharge to telephone interview was 225.0 days. The COVID-19 survivors' median ages were 69 years, and 51.3% were male. Among them, 29.9% had at least one clinical sequela. There were 19.2%, 22.7%, and 5.0% of the survivors reporting fatigue, respiratory symptoms, and cardiovascular symptoms, respectively. Comorbidities, disease severity, the application of mechanical ventilation and high-flow oxygen therapy, and the history of re-admission were associated with the presence of clinical sequelae. CONCLUSIONS: Our study provides further evidence for the prevalence and characteristics of clinical sequelae of COVID-19 survivors, suggesting long-term monitoring and management is needed for their full recovery.

Donor activating killer cell immunoglobulin-like receptors genes correlated with Epstein-Barr virus reactivation after haploidentical haematopoietic stem cell transplantation.

Natural killer (NK) cells exert anti-viral effects after haematopoietic stem cell transplantation (HSCT). The balance between inhibition and activation of NK cells determined by the inherited repertoire of killer cell immunoglobulin-like receptors (KIR) genes may influence Epstein-Barr virus (EBV) reactivation after transplantation. To evaluate the relative contributions of KIR genotypes to EBV reactivation, we prospectively enrolled 300 patients with malignant haematological disease who were suitable for haploidentical HSCT. Univariate analysis showed that donors with KIR2DS1, KIR2DS3 or KIR3DS1 genes were associated with an increased risk of EBV reactivation [hazard ratio (HR) 1·86, 95% confidence interval (CI) 1·19-2·9, P = 0·0067; HR 1·78, 95% CI 1·07-2·97, P = 0·027; HR 1·86, 95% CI 1·19-2·91, P = 0·0065 respectively]. Multivariate analysis revealed that the presence of KIR2DS1, KIR2DS3 or KIR3DS1 genes was associated with increased EBV reactivation after HSCT. This effect was more evident in the absence of the cognate ligands for the corresponding activating receptors. Our present data firstly showed that donors with activating KIR genes, specifically activating KIR2DS1, KIR2DS3 and KIR3DS1, had an increased risk of EBV reactivation. Precaution for patients whose donors carry activating genes will help prevent EBV reactivation and improve patient prognosis after HSCT.

Post-infection cognitive impairments in a cohort of elderly patients with COVID-19.

BACKGROUND: Understanding the long-term effects of coronavirus disease 2019 (COVID-19) on cognitive function is essential for monitoring the cognitive decline in the elderly population. This study aims to assess the current cognitive status and the longitudinal cognitive decline in elderly patients recovered from COVID-19. METHODS: This cross-sectional study recruited 1539 COVID-19 inpatients aged over 60 years who were discharged from three COVID-19-designated hospitals in Wuhan, China, from February 10 to April 10, 2020. In total, 466 uninfected spouses of COVID-19 patients were selected as controls. The current cognitive status was assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) and the longitudinal cognitive decline was assessed using an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Cognitive assessments were performed 6 months after patient discharge. RESULTS: Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores [TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.19 (3.00 to 3.63) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had lower TICS-40 scores and higher IQCODE scores than non-severe COVID-19 patients [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.63 (3.13 to 4.31) vs. 3.13 (3.00 to 3.56), p < 0.001] and controls [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR) 3.63 (3.13 to 4.31) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had a higher proportion of cases with current cognitive impairment and longitudinal cognitive decline than non-severe COVID-19 patients [dementia: 25 (10.50 %) vs. 9 (0.69 %), p < 0.001; Mild cognitive impairment (MCI): 60 (25.21 %) vs. 63 (4.84 %), p < 0.001] and controls [dementia: 25 (10.50 %) vs. 0 (0 %), p < 0.001; MCI: 60 (25.21 %) vs. 20 (4.29 %), p < 0.001)]. COVID-19 severity, delirium and COPD were risk factors of current cognitive impairment. Low education level, severe COVID-19, delirium, hypertension and COPD were risk factors of longitudinal cognitive decline. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with an increased risk of long-term cognitive decline in elderly population. COVID-19 patients, especially severe patients, should be intensively monitored for post-infection cognitive decline.