[Prognostic factors of extracorporeal membrane oxygenation in the treatment of severe pediatric acute respiratory distress syndrome].

Objective: To explore the factors affecting the prognosis of severe pediatric acute respiratory distress syndrome (ARDS) after receiving extracorporeal membrane oxygenation (ECMO) support. Methods: It was a multicenter prospective observational study. A total of 95 children with severe ARDS who were treated with ECMO salvage therapy from January 2018 to December 2022 in 9 pediatric ECMO centers in China were enrolled in the study. The general data, disease severity, organ function, comprehensive treatment and prognosis were recorded, and they were divided into survival group and death group according to the outcome at discharge. T test, chi-square test, multivariate Logistic regression and mixed linear model were used to analyze the relationship among baseline before ECMO treatment, some important indicators (pediatric critical scores, platelet count, albumin, fibrinogen, etc) during ECMO treatment and prognosis. Results: Among the 95 children with severe ARDS who received ECMO, 55 (58%) were males and 40 (42%) were females, aged 36.9 (0.5, 72.0) months. Twelve children (13%) were immunodeficient. Sixty-eight (72%) children were treated with venous artery (VA) mode and 27 (28%) with venous vein (VV) mode. The discharge survival rates of overall, VA, and VV mode children were 51% (48/95), 47% (32/68), and 59% (16/27), respectively. The number of immunodeficient children in the death group was higher, and there were lower pediatric critical scores, platelet count, albumin, fibrinogen and arterial oxygen partial pressure/fraction of inspired oxygen (PaO2/FiO2), higher ventilator driving pressure (ΔP), oxygenaion index (OI), and longer ARDS duration before ECMO (all P<0.05). There were no statistically significant differences in other indicators, including age, gender, weight, and ECMO mode among different prognostic groups (all P>0.05). High ΔP, high OI, low P/F, and low albumin were high-risk factors affecting prognosis(all P<0.05). After further grouping, it was found that ΔP≥25 cmH2O (1 cmH2O=0.098 kPa), P/F≤67 mmHg (1 mmHg=0.133 kPa) and OI≥35 were the thresholds for predicting poor prognosis (P<0.05). From 24 h after ECMO, there were significant differences in ΔP, P/F and OI between the dead group and the survival group (all P<0.05), and the differences gradually increased with the ECMO process. The platelet level was significant from 7 days after ECMO (P<0.05) and gradually expanded. Blood lactate levels showed a significant difference between the 2 groups on before and after ECMO (P<0.05) and gradually increased from 24 h after ECMO. Conclusions: The risk factors affecting the prognosis of severe ARDS in ECMO include high ΔP, high OI, low P/F and low albumin purification therapy before ECMO. The gradual decrease of ΔP, OI and increase of P/F from 24 h of ECMO predicted a good prognosis, while the gradual increase of lactate after ECMO application showed a poor prognosis.

[Analysis of genetic etiology of 234 deaths in the pediatric intensive care unit with suspected genetic diseases].

Objective: To explore the genetic etiology of pediatric intensive care unit (PICU) mortality cases and summarize their clinical characteristics. Methods: This was a retrospective cohort study. The study population consisted of 234 children who died within 7 d after admitted to the PICU of Children's Hospital of Fudan University from January 2017 to December 2021. The clinical diagnoses, laboratory test results, and genetic testing results were collected. These patients were divided into the pathogenic gene variation positive (PGVP) group and the pathogenic gene variation negative (PGVN) group according to the results of genetic testing. The Mann-Whitney U test and Pearson's chi-square test or Fisher's exact probability method were used to compare the clinical characteristics between the groups. Results: A total of 234 cases were enrolled, including 139 (59.4%) males and 95 (40.6%) females. The age at death was 1.0 (0.4, 3.7) years old and the length of PICU stay was 16 (6, 33) days. There were 62 cases (26.5%) PGVP, and the mutated pathogenic genes included immune genes (23 cases (37.1%)), metabolic genes (11 cases (17.7%)), neuromuscular genes (11 cases (17.7%)), cardiovascular genes (4 cases (6.5%)), and genes of other systems (13 cases (21.0%)). The age at death in PGVP cases was significantly lower than in PGVN cases (0.6 (0.3, 1.4) vs. 1.3(0.5, 4.3) years old, Z=3.85, P<0.001). Compared with the PGVN group, the PGVP group had a higher incidence of family history and chronic complex conditions (CCC) than the PGVN group (6.5% (4/62) vs. 0.6% (1/172) and 93.5% (58/62) vs. 76.2% (131/172), χ2=8.87, P=0.018 and 0.003, respectively). Children in the PGVP group were admitted with higher incidence of severe infection, decreased consciousness or coma, moderate-to-severe anemia, thrombocytopenia, protracted diarrhea, and abnormalities in muscle strength or tone than those in the PGVN group (74.2%(46/62) vs. 45.9%(79/172), 50.0%(31/62) vs. 35.5%(61/172), 32.3%(20/62) vs. 18.0%(31/172), 21.0%(13/62) vs. 10.5%(18/172), 25.8%(16/62) vs. 4.1%(7/172), 16.1%(10/62) vs. 5.2%(9/172), χ2=14.63, 4.04, 5.41, 4.37, 24.30, 7.25, all P<0.05). Pathogenic genes that occurred more than twice included IL2RG (5 cases), SMN1 (4 cases), and SH2D1A (3 cases, including 2 single gene varients and 1 copy number varient). Conclusions: Among the deceased cases in the PICU, the main genetic causes are immune-related, metabolic, and neuromuscular genetic disorders. Critically ill children with a family history, CCC, and early features such as severe infections, decreased consciousness or coma, moderate to severe anemia, thrombocytopenia, protracted diarrhea, or abnormalities in muscle strength or tone should be closely monitored and undergo early genetic testing.

Development of a Colorimetric Loop-Mediated Isothermal Amplification Assay for the Detection of Trypanosoma cruzi in Low-Resource Settings.

Chagas disease is an inflammatory parasitic infection caused by Trypanosoma cruzi (T. cruzi). Early diagnosis is crucial in guiding treatment and slowing disease progression; however, current diagnostic methods have insufficient detection limits and often require skilled technicians. Molecular tests, especially isothermal nucleic acid assays, are advantageous due to their excellent sensitivity, specificity, speed, and simplicity. Here, we optimized a colorimetric loop-mediated isothermal amplification (LAMP) assay for T. cruzi. We can detect as few as 2 genomic copies/reaction using three different T. cruzi strains. We examined selectivity using other parasitic protozoans and successfully detected T. cruzi DNA extracted from parasites in human whole blood down to 1.2 parasite equivalents/reaction. We also performed a blinded study using canine blood samples and established a 100% sensitivity, specificity, and accuracy for the colorimetric LAMP assay. Finally, we used a heated 3D printer bed and an insulated thermos cup to demonstrate that the LAMP incubation step could be performed with accessible, low-cost materials. Altogether, we have developed a high-performing assay for T. cruzi with a simple colorimetric output that would be ideal for rapid, low-cost screening at the point of use.

Association between garden work and risk of incident dementia in an older population in China: a national cohort study.

OBJECTIVES: Evidence on the association between garden work and risk of incident dementia in the older Chinese population is limited. This study aimed to explore the association between the frequency of garden work and risk of incident dementia in an older population in China. STUDY DESIGN: This was a national cohort study. METHODS: This study analysed data from 8676 participants (median age: 86 years) from the Chinese Longitudinal Healthy Longevity Survey. Cox proportional hazard models were used to assess the association between the frequency of garden work and risk of incident dementia using hazard ratios (HRs) and 95% confidence intervals (CIs). Multiplicative and additive interaction effects were calculated between the frequency of garden work and age, sex or residence on incident dementia; subgroup analyses of the association were also conducted by age, sex and residence. In addition, sensitivity analyses were performed to assess the robustness of the results. RESULTS: During 4.31 years (median) of follow-up, 633 participants developed dementia. Compared with participants who did not engage in garden work, the adjusted risk of incident dementia for those who regularly or almost daily engaged in garden work decreased by 28% (HR = 0.72, 95% CI: 0.57-0.93). An additive interaction effect between frequency of garden work and age on incident dementia was observed, with subgroup analyses demonstrating similar statistically significant associations among participants aged ≥85 years, women and city or town residents. Sensitivity analyses were consistent with the primary analysis in the present study. CONCLUSIONS: Frequent engagement in garden work may be associated with a reduced risk of dementia and may be an effective measure to prevent incident dementia in the older population in China.

[Investigation of Anisakis infections in coastal marine fishes and awareness of anisakiasis control knowledge among residents in Yantai City in 2021].

OBJECTIVE: To investigate the prevalence of Anisakis infections in coastal marine fishes and awareness of anisakiasis control knowledge among local residents in Yantai City, Shandong Province in 2021, so as to provide insights into formulation of anisakiasis control interventions. METHODS: Marine fishes were purchased from Shunxin Port, Yantai City, Shandong Province in November 2021, and the presence of Anisakis was detected in different species of fishes and different fish sites. The correlations between body length and weight of marine fish and intensity of Anisakis infections were examined using Spearman's rank correlation analysis, and the dietary habits and anisakiasis control knowledge were investigated using questionnaire surveys among local residents. RESULTS: A total of 201 marine fishes belonging to 20 species were dissected, and Anisakis was detected in 77 marine fishes (38.31%) belonging to 11 species (55.00%), with a mean infection intensity of 45.04 parasites per fish (3 468/77). Spearman's rank correlation analysis revealed that the body length (rs = 0.74, P < 0.05) and weight (rs = 0.79, P < 0.01) of the monkfish correlated positively with the intensity of Anisakis infections, and the body length (rs = 0.68, P < 0.05) of the flatfish correlated positively with the intensity of Anisakis infections, while no correlations were examined between the body length or weight of other marine fishes and the intensity of Anisakis infections. Of all respondents, 53.38% men and 56.67% women did not know anisakiasis control knowledge at all, and there was a significant difference in the proportion of respondents using separate chopping boards for raw and cooked food from different villages (χ2 = 17.89, P < 0.01), while there was an age-specific proportion of respondents with habitats of eating raw or semi-raw seafood (χ2 = 28.27, P < 0.01). CONCLUSIONS: The prevalence and intensity of Anisakis infections were high in coastal marine fishes in Yantai City in 2021, and the awareness of anisakiasis control knowledge was low among local residents. Intensified health education pertaining to anisakiasis control knowledge is recommended to reduce the risk of Anisakis infections.

LLPS of FXR proteins drives replication organelle clustering for ß-coronaviral proliferation.

ß-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal that host fragile X-related (FXR) family proteins (FXR1/FXR2/FMR1) are required for DMV clustering induced by expression of viral non-structural proteins (Nsps) Nsp3 and Nsp4. Depleting FXRs results in DMV dispersion in the cytoplasm. FXR1/2 and FMR1 are recruited to DMV sites via specific interaction with Nsp3. FXRs form condensates driven by liquid-liquid phase separation, which is required for DMV clustering. FXR1 liquid droplets concentrate Nsp3 and Nsp3-decorated liposomes in vitro. FXR droplets facilitate recruitment of translation machinery for efficient translation surrounding DMVs. In cells depleted of FXRs, SARS-CoV-2 replication is significantly attenuated. Thus, SARS-CoV-2 exploits host FXR proteins to cluster viral DMVs via phase separation for efficient viral replication.

Stay in touch with the endoplasmic reticulum.

The endoplasmic reticulum (ER), which is composed of a continuous network of tubules and sheets, forms the most widely distributed membrane system in eukaryotic cells. As a result, it engages a variety of organelles by establishing membrane contact sites (MCSs). These contacts regulate organelle positioning and remodeling, including fusion and fission, facilitate precise lipid exchange, and couple vital signaling events. Here, we systematically review recent advances and converging themes on ER-involved organellar contact. The molecular basis, cellular influence, and potential physiological functions for ER/nuclear envelope contacts with mitochondria, Golgi, endosomes, lysosomes, lipid droplets, autophagosomes, and plasma membrane are summarized.

Opportunities and challenges of tackling Scope 3 "Indirect" emissions from residential hot water.

The water sector could play a major role towards a Net Zero greenhouse gas (GHG) future if Scope 3 emissions were embraced and operationalised. Significant opportunities and challenges exist in tackling Scope 3 emissions including those associated with customer hot water use. Present GHG emission reduction practices predominantly focus on Scope 1 "within utility" and Scope 2 "purchased energy" emissions. In the urban water cycle, Scope 3 "indirect" emissions dominate, and water use is only one example of Scope 3 emissions. Over 90% of all water cycle GHG emissions can be attributed to water use in residential, industrial and commercial premises, collectively some 7% of global GHG emissions. One possibility is for water utilities to actively support efficient hot water use such as new ultra-low flow shower heads. Scope 3 opportunities also offer a range of cost-effective emissions-reduction opportunities, particularly when the wider perspective of "community value" is considered and not just a "business financial perspective". Hot water efficiency is additionally essential to Net Zero carbon futures, even with decarbonised grids, because most major Net Zero roadmaps require energy efficiency gains. Scientific and management advance needed includes: accounting methodologies, clear roles, collaboration, new business models, and clear definitions. The water sector has the opportunity to play a significant role in achieving Net Zero cities. The decision how much is yet to be made.

[Construction and evaluation of a nomogram for predicting the prognosis of patients with colorectal cancer with peritoneal carcinomatosis treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy].

Objectives: To construct a nomogram incorporating important prognostic factors for predicting the overall survival of patients with colorectal cancer with peritoneal metastases treated with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), the aim being to accurately predict such patients' survival rates. Methods: This was a retrospective observational study. Relevant clinical and follow-up data of patients with colorectal cancer with peritoneal metastases treated by CRS + HIPEC in the Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University from 2007 January to 2020 December were collected and subjected to Cox proportional regression analysis. All included patients had been diagnosed with peritoneal metastases from colorectal cancer and had no detectable distant metastases to other sites. Patients who had undergone emergency surgery because of obstruction or bleeding, or had other malignant diseases, or could not tolerate treatment because of severe comorbidities of the heart, lungs, liver or kidneys, or had been lost to follow-up, were excluded. Factors studied included: (1) basic clinicopathological characteristics; (2) details of CRS+HIPEC procedures; (3) overall survival rates; and (4) independent factors that influenced overall survival; the aim being to identify independent prognostic factors and use them to construct and validate a nomogram. The evaluation criteria used in this study were as follows. (1) Karnofsky Performance Scale (KPS) scores were used to quantitatively assess the quality of life of the study patients. The lower the score, the worse the patient's condition. (2) A peritoneal cancer index (PCI) was calculated by dividing the abdominal cavity into 13 regions, the highest score for each region being three points. The lower the score, the greater is the value of treatment. (3) Completeness of cytoreduction score (CC), where CC-0 and CC-1 denote complete eradication of tumor cells and CC-2 and CC-3 incomplete reduction of tumor cells. (4) To validate and evaluate the nomogram model, the internal validation cohort was bootstrapped 1000 times from the original data. The accuracy of prediction of the nomogram was evaluated with the consistency coefficient (C-index), and a C-index of 0.70-0.90 suggest that prediction by the model was accurate. Calibration curves were constructed to assess the conformity of predictions: the closer the predicted risk to the standard curve, the better the conformity. Results: The study cohort comprised 240 patients with peritoneal metastases from colorectal cancer who had undergone CRS+HIPEC. There were 104 women and 136 men of median age 52 years (10-79 years) and with a median preoperative KPS score of 90 points. There were 116 patients (48.3%) with PCI≤20 and 124 (51.7%) with PCI>20. Preoperative tumor markers were abnormal in 175 patients (72.9%) and normal in 38 (15.8%). HIPEC lasted 30 minutes in seven patients (2.9%), 60 minutes in 190 (79.2%), 90 minutes in 37 (15.4%), and 120 minutes in six (2.5%). There were 142 patients (59.2%) with CC scores 0-1 and 98 (40.8%) with CC scores 2-3. The incidence of Grade III to V adverse events was 21.7% (52/240). The median follow-up time is 15.3 (0.4-128.7) months. The median overall survival was 18.7 months, and the 1-, 3- and 5-year overall survival rates were 65.8%, 37.2% and 25.7%, respectively. Multivariate analysis showed that KPS score, preoperative tumor markers, CC score, and duration of HIPEC were independent prognostic factors. In the nomogram constructed with the above four variables, the predicted and actual values in the calibration curves for 1, 2 and 3-year survival rates were in good agreement, the C-index being 0.70 (95% CI: 0.65-0.75). Conclusions: Our nomogram, which was constructed with KPS score, preoperative tumor markers, CC score, and duration of HIPEC, accurately predicts the survival probability of patients with peritoneal metastases from colorectal cancer treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy.

Non-linear relationship between dietary vitamin E intake and cognitive performance in older adults.

OBJECTIVES: This study aimed to explore the relationship between dietary vitamin E (VE) intake and cognitive function in older adults. STUDY DESIGN: This was a cross-sectional study. METHODS: We applied data from the National Health and Nutrition Examination Survey obtained during 2011-2014 that met our requirements. The cognitive ability assessments included the Consortium to Establish a Registry for Alzheimer's Disease Word Learning (CERAD-WL) and Delayed Recall (CERAD-DR) tests, the animal fluency test, the Digit Symbol Substitution Test, and a composite z-score calculated by summing z-scores of individual tests. We used binary logistic regression analysis to explore the relationship between VE intake and cognitive performance. The results are reported using odds ratios and 95% confidence intervals. Our study also included sex-stratified analyses and sensitivity analysis. A restricted cubic splines model was used to evaluate the dose-response relationship between dietary VE intake and cognitive function. RESULTS: This study found that a higher intake of dietary VE was associated with a lower risk of cognitive impairment in patients. Sensitivity analysis shows stable results. The results of the gender stratification analysis showed that dietary VE intake was negatively related to the risk of cognitive disorder among females. An irregular L-shaped dose-response relationship was observed between dietary VE intake and cognitive impairment risk. CONCLUSIONS: Dietary VE intake was negatively related to the risk of cognitive disorder in older adults, with a higher VE intake lowering the risk.

DMV biogenesis during ß-coronavirus infection requires autophagy proteins VMP1 and TMEM41B.

Upon entering host cells, ß-coronaviruses specifically induce generation of replication organelles (ROs) from the endoplasmic reticulum (ER) through their nonstructural protein 3 (nsp3) and nsp4 for viral genome transcription and replication. The most predominant ROs are double-membrane vesicles (DMVs). The ER-resident proteins VMP1 and TMEM41B, which form a complex to regulate autophagosome and lipid droplet (LD) formation, were recently shown to be essential for ß-coronavirus infection. Here we report that VMP1 and TMEM41B contribute to DMV generation but function at different steps. TMEM41B facilitates nsp3-nsp4 interaction and ER zippering, while VMP1 is required for subsequent closing of the paired ER into DMVs. Additionally, inhibition of phosphatidylserine (PS) formation by siPTDSS1 partially reverses the DMV and LD defects in VMP1 KO cells, suggesting that appropriate PS levels also contribute to DMV formation. This work provides clues to the mechanism of how host proteins collaborate with viral proteins for endomembrane reshaping to promote viral infection.

The Siberian pine growth dynamics in Altai Mountains, China

Abstract Climatic factors play an essential role in the growth of tree ring width. In this study, we aimed to evaluate the correlation between climatic variables and tree-ring growth characteristics of Pinus sibirica in Altai mountains, northwestern China. This study being is first of its kind on climate growth analysis of Pinus sibirica in northwestern China. The study showed great potential to understand the species growing under the specific climatic conditions. Total of 70 tree cores collected from three sites in the sampling area, out of which 63 tree cores considered for this study. The effect of climatic variables which was studied include precipitation, temperature and PDSI. Our results showed that Tree Ring Width chronology has a significantly positive correlation with the late winter (March) temperature and significant negative correlation with the July temperatures. A significant correlation was observed with the late summer precipitation whereas no significant relation found with the Palmer Drought Severity Index. These significant correlations with temperature and precipitation suggested that this tree species had the potential for the reconstruction of the past climate in the area.

RESUMO Fatores climáticos desempenham papel essencial no crescimento da largura dos anéis das árvores. Neste estudo, objetivou-se avaliar a correlação entre variáveis climáticas e características de crescimento de anéis de árvores de Pinus sibirica nas montanhas de Altai, noroeste da China. Este estudo é o primeiro desse tipo na análise do crescimento climático de Pinus sibirica no noroeste da China. O estudo mostrou grande potencial para entender as espécies que crescem sob as condições climáticas específicas. Total de 70 testemunhos coletados em três locais na área de amostragem, dos quais 63 testemunhos considerados para este estudo. O efeito das variáveis climáticas estudadas incluem precipitação, temperatura e PDSI. Nossos resultados mostraram que a cronologia da Largura do Anel da Árvore tem uma correlação significativamente positiva com a temperatura do final do inverno (março) e uma correlação negativa significativa com as temperaturas de julho. Uma correlação significativa foi observada com a precipitação do final do verão, enquanto nenhuma relação significativa foi encontrada com o Índice de Severidade de Seca de Palmer. Essas correlações significativas com a temperatura e precipitação sugeriram que esta espécie de árvore tinha o potencial para a reconstrução do clima passado na área.

The Siberian pine growth dynamics in Altai Mountains, China / A dinâmica de crescimento do pinheiro siberiano nas montanhas de Altai, China

Climatic factors play an essential role in the growth of tree ring width. In this study, we aimed to evaluate the correlation between climatic variables and tree-ring growth characteristics of Pinus sibirica in Altai mountains, northwestern China. This study being is first of its kind on climate growth analysis of Pinus sibirica in northwestern China. The study showed great potential to understand the species growing under the specific climatic conditions. Total of 70 tree cores collected from three sites in the sampling area, out of which 63 tree cores considered for this study. The effect of climatic variables which was studied include precipitation, temperature and PDSI. Our results showed that Tree Ring Width chronology has a significantly positive correlation with the late winter (March) temperature and significant negative correlation with the July temperatures. A significant correlation was observed with the late summer precipitation whereas no significant relation found with the Palmer Drought Severity Index. These significant correlations with temperature and precipitation suggested that this tree species had the potential for the reconstruction of the past climate in the area.

Fatores climáticos desempenham papel essencial no crescimento da largura dos anéis das árvores. Neste estudo, objetivou-se avaliar a correlação entre variáveis climáticas e características de crescimento de anéis de árvores de Pinus sibirica nas montanhas de Altai, noroeste da China. Este estudo é o primeiro desse tipo na análise do crescimento climático de Pinus sibirica no noroeste da China. O estudo mostrou grande potencial para entender as espécies que crescem sob as condições climáticas específicas. Total de 70 testemunhos coletados em três locais na área de amostragem, dos quais 63 testemunhos considerados para este estudo. O efeito das variáveis climáticas estudadas incluem precipitação, temperatura e PDSI. Nossos resultados mostraram que a cronologia da Largura do Anel da Árvore tem uma correlação significativamente positiva com a temperatura do final do inverno (março) e uma correlação negativa significativa com as temperaturas de julho. Uma correlação significativa foi observada com a precipitação do final do verão, enquanto nenhuma relação significativa foi encontrada com o Índice de Severidade de Seca de Palmer. Essas correlações significativas com a temperatura e precipitação sugeriram que esta espécie de árvore tinha o potencial para a reconstrução do clima passado na área.

[Clinicopathological and molecular features of multinodular and vacuolating neuronal tumors of the cerebrum].

Objective: To investigate clinicopathological features of multinodular and vacuolar neurodegenerative tumor (MVNT) of the cerebrum, and to investigate its immunophenotype, molecular characteristics and prognosis. Methods: Four cases were collected at the General Hospital of Southern Theater Command, Guangzhou, China and one case was collected at the First People's Hospital of Huizhou, China from 2013 to 2021. Clinical, histological, immunohistochemical and molecular characteristics of these five cases were analyzed. Follow-up was carried out to evaluate their prognoses. Results: There were four females and one male, with an average age of 42 years (range, 17 to 51 years). Four patients presented with seizures, while one presented with discomfort on the head. Pre-operative imaging demonstrated non-enhancing, T2-hyperintense multinodular lesions in the deep cortex and superficial white matter of the frontal (n=1) or temporal lobes (n=4). Microscopically, the tumor cells were mostly arranged in discrete and coalescent nodules primarily within the deep cortical ribbon and superficial subcortical white matter. The tumors were composed of large cells with ganglionic morphology, vesicular nuclei, prominent nucleoli and amphophilic or lightly basophilic cytoplasm. They exhibited varying degrees of matrix vacuolization. Vacuolated tumor cells did not show overt cellular atypia or any mitotic activities. Immunohistochemically, tumor cells exhibited widespread nuclear staining for the HuC/HuD neuronal antigens, SOX10 and Olig2. Expression of other neuronal markers, including synaptophysin, neurofilament and MAP2, was patchy to absent. The tumor cells were negative for NeuN, GFAP, p53, H3K27M, IDH1 R132H, ATRX, BRG1, INI1 and BRAF V600E. No aberrant molecular changes were identified in case 3 and case 5 using next-generation sequencing (including 131 genes related to diagnosis and prognosis of central nervous system tumors). All patients underwent complete or substantial tumor excision without adjuvant chemoradiotherapy. Post-operative follow-up information over intervals of 6 months to 8 years was available for five patients. All patients were free of recurrence. Conclusions: MVNT is an indolent tumor, mostly affecting adults, which supports classifying MVNT as WHO grade 1. There is no tumor recurrence even in the patients treated with subtotal surgical excision. MVNTs may be considered for observation or non-surgical treatments if they are asymptomatic.

[Clinical study of heparin anticoagulation scheme during plasma adsorption therapy for liver failure].

Objective: To investigate the reasonable dosage of heparin anticoagulation scheme during plasma adsorption (PA) therapy for liver failure. Methods: Patients with liver failure treated with PA therapy were retrospectively collected and divided according to the anticoagulation scheme into the first-dose heparin anticoagulation group and the first-dose plus maintenance heparin anticoagulation group. Clinical data and laboratory test results were compared before and after treatment between the two groups. Paired t-tests were used for comparison within the normally distributed groups. An independent two-sample t-test was used for inter group comparison. Wilcoxon rank-sum test was used for measurement data that did not conform to a normal distribution. Fisher's exact test was used to compare the count data between groups. Results: There were 138 cases with liver failure treated with PA therapy from October 2017 to September 2020. Among them, 83 and 55 cases were in the first-dose heparin anticoagulation and first-dose plus maintenance heparin anticoagulation group, respectively. Age, gender, and laboratory data before treatment were comparable between the two groups. PA treatment was successfully completed in both groups of patient, and there was no statistically significant difference in the determination of coagulation level with plasma separators (Z=-0.15, P=0.216). There were different degrees of bleeding complications in both groups. In the first-dose heparin anticoagulation group, there were two cases (2.4%) of central venous catheter bleeding and one case (1.2%) of epistaxis. In the first-dose plus maintenance heparin anticoagulation group, there were five cases (9.1%) of central venous catheter bleeding, two cases (3.6%) of skin bleeding, one case (1.8%) of epistaxis, and one case (1.8%) of upper gastrointestinal bleeding. The incidence of bleeding complications was lower in the first-dose of heparin anticoagulation than first-dose plus maintenance heparin anticoagulation group, and the difference was statistically significant (P<0.001). The activated partial thromboplastin time of the two groups was prolonged after therapy withdrawal than with therapy, and the difference was statistically significant (first-dose heparin anticoagulation group: t=3.850, P=0.022; first-dose plus maintenance heparin anticoagulation group: t=6.733, P=0.007). The activated partial thromboplastin time was prolonged in patients with first-dose plus maintenance heparin anticoagulation than first-dose heparin anticoagulation group, and the difference was statistically significant (P=0.025). The total bilirubin of the two groups before and after PA was significantly changed (the first-dose heparin anticoagulation group: Z=-2.455, P=0.017; the first-dose plus maintenance heparin anticoagulation group: Z=-2.307, P=0.024), and there was no statistically significant difference between the two groups (P=0.412). There was no statistically significant difference in platelet changes before and after PA therapy between the two groups (the first dose of heparin anticoagulation group: Z=-0.529, P=0.480; the first-dose plus maintenance heparin anticoagulation group: Z=-0.276, P=0.362). Conclusion: Anticoagulation scheme without maintenance medication is feasible with prothrombin activity before ≤20-40%, activated partial thromboplastin time of ≤87 s (2 times the upper normal value), platelet count before treatment (excluding contraindications to heparin) ≥50×109/L, and the first dose of heparin administration of 0.2 mg/kg during PA therapy in patients with liver failure.

Features and clinical significance of tertiary lymphoid structure in cutaneous squamous cell carcinoma.

BACKGROUND: Tertiary lymphoid structure (TLS) plays an important role in antitumour immunity, largely reflecting the prognosis. However, its clinical implication in cutaneous squamous cell carcinoma (cSCC) remains unknown. OBJECTIVES: To explore the features of TLS in cSCC and its association with clinicopathological characteristics. METHODS: Two independent RNA-seq data of cSCC were used to investigate the tumour immune microenvironment, as well as TLS-related chemokines and cytokines. The density and location of TLSs were assessed in a total of 82 cSCC patients, and the clinicopathologic association was examined. RESULTS: Bioinformatics analysis showed that a large amount of immune cell infiltration and significant up-regulation of TLS-related chemokines were observed in cSCC. Histologically, TLSs appeared as highly organized structures in 72 (87.8%) cases with different levels of density and maturation, among which 14 cases were in low-density group and 58 cases were in high-density group. Clinically, the presence of TLS was prominently associated with better degree of histopathological grades and higher level of sun exposure. Furthermore, the presence of intratumoral TLS was associated with lower lymphovascular invasion. CONCLUSIONS: TLS is highly organized in cSCC, and the presence of TLS is a positive prognostic factor for cSCC, which will provide a theoretical basis for the future diagnostic and therapeutic value in cSCC.

VMP1 and TMEM41B are essential for DMV formation during ß-coronavirus infection.

ß-coronaviruses reshape host cell endomembranes to form double-membrane vesicles (DMVs) for genome replication and transcription. Ectopically expressed viral nonstructural proteins nsp3 and nsp4 interact to zipper and bend the ER for DMV biogenesis. Genome-wide screens revealed the autophagy proteins VMP1 and TMEM41B as important host factors for SARS-CoV-2 infection. Here, we demonstrated that DMV biogenesis, induced by virus infection or expression of nsp3/4, is impaired in the VMP1 KO or TMEM41B KO cells. In VMP1 KO cells, the nsp3/4 complex forms normally, but the zippered ER fails to close into DMVs. In TMEM41B KO cells, the nsp3-nsp4 interaction is reduced and DMV formation is suppressed. Thus, VMP1 and TMEM41B function at different steps during DMV formation. VMP1 was shown to regulate cross-membrane phosphatidylserine (PS) distribution. Inhibiting PS synthesis partially rescues the DMV defects in VMP1 KO cells, suggesting that PS participates in DMV formation. We provide molecular insights into the collaboration of host factors with viral proteins to remodel host organelles.

Endomembrane remodeling in SARS-CoV-2 infection.

During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the viral proteins intimately interact with host factors to remodel the endomembrane system at various steps of the viral lifecycle. The entry of SARS-CoV-2 can be mediated by endocytosis-mediated internalization. Virus-containing endosomes then fuse with lysosomes, in which the viral S protein is cleaved to trigger membrane fusion. Double-membrane vesicles generated from the ER serve as platforms for viral replication and transcription. Virions are assembled at the ER-Golgi intermediate compartment and released through the secretory pathway and/or lysosome-mediated exocytosis. In this review, we will focus on how SARS-CoV-2 viral proteins collaborate with host factors to remodel the endomembrane system for viral entry, replication, assembly and egress. We will also describe how viral proteins hijack the host cell surveillance system-the autophagic degradation pathway-to evade destruction and benefit virus production. Finally, potential antiviral therapies targeting the host cell endomembrane system will be discussed.