Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Convalescent Plasma in Critically Ill Patients With COVID-19: An Observational Study

Background: Convalescent plasma is a potential therapeutic option for critically ill patients with coronavirus disease 19 (COVID-19), yet its efficacy remains to be determined. The aim was to investigate the effects of convalescent plasma (CP) in critically ill patients with COVID-19. Methods: This was a single-center prospective observational study conducted in Rio de Janeiro, Brazil, from March 17th to May 30th, with final follow-up on June 30th. We included 113 laboratory-confirmed COVID-19 patients with respiratory failure. Primary outcomes were time to clinical improvement and survival within 28 days. Secondary outcomes included behavior of biomarkers and viral loads. Kaplan–Meier analyses and Cox proportional-hazards regression using propensity score with inverse-probability weighing were performed. Results: 41 patients received CP and 72 received standard of care (SOC). Median age was 61 years (IQR 48–68), disease duration was 10 days (IQR 6–13), and 86% were mechanically ventilated. At least 29 out of 41CP-recipients had baseline IgG titers ≥ 1:1,080. Clinical improvement within 28 days occurred in 19 (46%) CP-treated patients, as compared to 23 (32%) in the SOC group [adjusted hazard ratio (aHR) 0.91 (0.49–1.69)]. There was no significant change in 28-day mortality (CP 49% vs. SOC 56%; aHR 0.90 [0.52–1.57]). Biomarker assessment revealed reduced inflammatory activity and increased lymphocyte count after CP. Conclusions: In this study, CP was not associated with clinical improvement or increase in 28-day survival. However, our study may have been underpowered and included patients with high IgG titers and life-threatening disease. Clinical Trial Registration: The study protocol was retrospectively registered at the Brazilian Registry of Clinical Trials (ReBEC) with the identification RBR-4vm3yy (http://www.ensaiosclinicos.gov.br).
Switching From Immediate-Release to Fractionated Dual-Release Hydrocortisone May Improve Metabolic Control and QoL in Selected Primary Adrenal Insufficiency Patients

Objective The use of once-daily dual-release HC (DR-HC) in primary adrenal insufficiency (PAI) is often associated with benefits in metabolic parameters when compared to immediate-release HC (IR-HC). In this study, we evaluated the effects on clinical, biochemical and metabolic parameters of switching from IR-HC to lower-dose DR-HC given both in once and fractionated daily doses. Methods Twenty autoimmune-PAI subjects were included. Patients on 30 mg/day divided in three doses IR-HC regimen (group A) were switched to DR-HC 25 mg/day given in two daily doses (20 mg in the morning and 5 mg at 2.00 p.m.); patients on 25 mg/day divided in two doses IR-HC regimen (group B) were switched to DR-HC 20 mg once daily. Biochemical and metabolic parameters, BMI and quality of life (QoL) were evaluated at the baseline and six months after the switch. Results Our small non-randomized study with short follow up showed significant benefits in both group A and group B without any apparent side-effects. After the switch to DR-HC, a significant decrease in adrenocorticotropic hormone (ACTH), HbA1c, total cholesterol, triglycerides, LDL, cholesterol, BMI as well as a significant improvement in QoL, were observed in both groups. At 6 months, ACTH levels were lower in group A while HbA1C and total cholesterol were lower in group B. Conclusion The DR-HC is a valid and effective therapeutic strategy to improve the metabolic control and the QoL in PAI. The reduction of ACTH levels with DR-HC regimens reflects a better biochemical control of PAI, obtained by using a lower dose and more physiological HC formulation. Both once-daily and fractionated daily doses of DR-HC showed advantages compared with IR-HC formulation.
Entrenched Inequalities? Class, Gender and Ethnic Differences in Educational and Occupational Attainment in England

Research in social stratification tends to focus on class differences in educational and occupational attainment, with particular attention to primary and secondary effects in the former, and class reproduction in the latter, domain. Research in ethnic studies tends to focus, however, on ethnic penalty or premium. Many studies have been conducted in each tradition on specific issues but little research is available that examines class, gender and ethnic effects simultaneously or in tandem with contextual effects, let alone on the whole trajectory from compulsory schooling, through further and higher education, to labor market position. Using data from the Longitudinal Study of Young People in England, this paper shows pronounced class differences but remarkable gender progress in each of the educational domains. With regard to ethnicity, people from minority ethnic heritages had lower GCSE scores due to poorer family conditions but achieved higher transition rates to A-Level study, higher university enrollment and, for some groups, greater attendance at elite universities, resulting in an overall higher rate of degree-level attainment than did whites. One might expect members of ethnic minority backgrounds to fare equally well in their earlier careers in the labor market, but only to find them more vulnerable to unemployment, less likely to have earnings, and more disadvantaged in terms of disposable incomes.
Functional Connectivity of Nucleus Accumbens and Medial Prefrontal Cortex With Other Brain Regions During Early-Abstinence Is Associated With Alcohol Dependence and Relapse: A Resting-Functional Magnetic Resonance Imaging Study

Background: Alcohol dependence (AD) is a chronic recurrent brain disease that causes a heavy disease burden worldwide, partly due to high relapse rates after detoxification. Verified biomarkers are not available for AD and its relapse, although the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) may play important roles in the mechanism of addiction. This study investigated AD- and relapse-associated functional connectivity (FC) of the NAc and mPFC with other brain regions during early abstinence. Methods: Sixty-eight hospitalized early-abstinence AD male patients and 68 age- and education-matched healthy controls (HCs) underwent resting-functional magnetic resonance imaging (r-fMRI). Using the NAc and mPFC as seeds, we calculated changes in FC between the seeds and other brain regions. Over a follow-up period of 6 months, patients were measured with the Alcohol Use Disorder Identification Test (AUDIT) scale to identify relapse outcomes (AUDIT ≥ 8). Results: Thirty-five (52.24%) of the AD patients relapsed during the follow-up period. AD displayed lower FC of the left fusiform, bilateral temporal superior and right postcentral regions with the NAc and lower FC of the right temporal inferior, bilateral temporal superior, and left cingulate anterior regions with the mPFC compared to controls. Among these FC changes, lower FC between the NAc and left fusiform, lower FC between the mPFC and left cingulate anterior cortex, and smoking status were independently associated with AD. Subjects in relapse exhibited lower FC of the right cingulate anterior cortex with NAc and of the left calcarine sulcus with mPFC compared to non-relapsed subjects; both of these reductions in FC independently predicted relapse. Additionally, FC between the mPFC and right frontal superior gyrus, as well as years of education, independently predicted relapse severity. Conclusion: This study found that values of FC between selected seeds (i.e., the NAc and the mPFC) and some other reward- and/or impulse-control-related brain regions were associated with AD and relapse; these FC values could be potential biomarkers of AD or for prediction of relapse. These findings may help to guide further research on the neurobiology of AD and other addictive disorders.
Species Identification in the Rhododendron vernicosum–R. decorum Species Complex (Ericaceae)

Delimitating species boundaries is the primary aim of biological classification and could be critical for evaluating the evolving process of species and conserving biodiversity. Rhododendron is an iconic group with an extraordinary diversity in southwest China. However, it remains unknown whether the recorded species therein comprise independently evolving lineages or artificially delimitated morphological entities. In this study, we carried out species delimitation of four Rhododendron species in the R. vernicosum-R. decorum species complex based on morphological analyses and population genetic data from nuclear simple sequence repeats (SSR) markers. We randomly selected a total of 105 specimens of different individuals identified as four species across their distributional ranges to examine the statistically distinct phenotypic clusters based on 19 morphological traits. Similarly, we genotyped 55 individuals of four species from 21 populations using 15 SSR markers. The morphological analyses sorted R. decorum and the other three species into two different phenotypic clusters. The genetic clusters were consistent with the morphological clusters. However, we also recovered the third genetic cluster, comprising six R. vernicosum populations and containing the admixed genetic compositions of the other two distinct genetic clusters. This hybrid group was morphologically similar to the typical R. vernicosum (including the samples from its type specimen locality and both R. verruciferum and R. gonggashanense) but with more genetic ancestry from R. decorum. Based on our findings, we identify two distinct species and one putative hybrid group due to introgression in the R. vernicosum-R. decorum species complex. We propose to merge R. verruciferum and R. gonggashanense into R. vernicosum based on genetic compositions and our morphological analyses. The hybrid group inferred from our findings, however, needs further investigations.
Prognostic Accuracy of Early Warning Scores for Clinical Deterioration in Patients With COVID-19

Background: Early Warning Scores (EWS), including the National Early Warning Score 2 (NEWS2) and Modified NEWS (NEWS-C), have been recommended for triage decision in patients with COVID-19. However, the effectiveness of these EWS in COVID-19 has not been fully validated. The study aimed to investigate the predictive value of EWS to detect clinical deterioration in patients with COVID-19. Methods: Between February 7, 2020 and February 17, 2020, patients confirmed with COVID-19 were screened for this study. The outcomes were early deterioration of respiratory function (EDRF) and need for intensive respiratory support (IRS) during the treatment process. The EDRF was defined as changes in the respiratory component of the sequential organ failure assessment (SOFA) score at day 3 (ΔSOFAresp = SOFA resp at day 3–SOFAresp on admission), in which the positive value reflects clinical deterioration. The IRS was defined as the use of high flow nasal cannula oxygen therapy, noninvasive or invasive mechanical ventilation. The performances of EWS including NEWS, NEWS 2, NEWS-C, Modified Early Warning Scores (MEWS), Hamilton Early Warning Scores (HEWS), and quick sepsis-related organ failure assessment (qSOFA) for predicting EDRF and IRS were compared using the area under the receiver operating characteristic curve (AUROC). Results: A total of 116 patients were included in this study. Of them, 27 patients (23.3%) developed EDRF and 24 patients (20.7%) required IRS. Among these EWS, NEWS-C was the most accurate scoring system for predicting EDRF [AUROC 0.79 (95% CI, 0.69–0.89)] and IRS [AUROC 0.89 (95% CI, 0.82–0.96)], while NEWS 2 had the lowest accuracy in predicting EDRF [AUROC 0.59 (95% CI, 0.46–0.720)] and IRS [AUROC 0.69 (95% CI, 0.57–0.81)]. A NEWS-C ≥ 9 had a sensitivity of 59.3% and a specificity of 85.4% for predicting EDRF. For predicting IRS, a NEWS-C ≥ 9 had a sensitivity of 75% and a specificity of 88%. Conclusions: The NEWS-C was the most accurate scoring system among common EWS to identify patients with COVID-19 at risk for EDRF and need for IRS. The NEWS-C could be recommended as an early triage tool for patients with COVID-19.
Supraphysiological Levels of IL-2 in Jak3-Deficient Mice Promote Strong Proliferative Responses of Adoptively Transferred Naive CD8+ T Cells

The antigen-independent, strong proliferative responses of naive CD8+ T cells have been well demonstrated in a particular strain of mice lacking IL-2 receptors. This type of proliferation is mainly driven by common gamma-chain (γc) cytokines, such as IL-2, IL-7, and IL-15, present at abnormally high levels in these mice. Similarly, in the present study, we showed that mice lacking Janus kinase 3 (Jak3), a tyrosine kinase crucial for γc cytokine signaling, could induce strong proliferation of adoptively transferred naive CD8+ T cells. This proliferation was also independent of antigenic stimulation, but heavily dependent on IL-2, as evidenced by the failure of proliferation of adoptively transferred IL-2 receptor alpha- and beta-chain-deficient naive CD8+ T cells. Consistent with this, Jak3 –/– mice showed elevated serum levels of IL-2 compared to wild-type mice, and interestingly, IL-2 production was due to high levels of accumulation of activated CD4+ T cells in Jak3 –/– mice along with defective CD4+ T regulatory cells. Collectively, these findings reveal previously unidentified unique immune contexts of Jak3 –/– mice that cause robust IL-2-driven T cell expansion and have a clinical implication for designing a treatment strategy for human patients with loss-of-function genetic mutations of Jak3.
“He’s Just a Wee Laddie”: The Relative Age Effect in Male Scottish Soccer

Significant structural, developmental, and financial constraints exist in Scottish soccer that may predicate a different approach to talent identification and development. To our knowledge, no published reports exist evaluating the prevalence of the relative age effect (RAE) in Scottish soccer players. Consequently, the aim of this study was to investigate the prevalence of the RAE among varied playing levels and ages of male Scottish youth soccer players. Birthdates of male youth players (n = 1,230) from U10 to U17 age groups and from playing levels: “Amateur” (n = 482), “Development” (n = 214), and “Performance” (n = 534), alongside a group of male Scottish senior professional players (n = 261) were recorded and categorized into quartiles (Q1 = January–March; Q2 = April–June; Q3 = July–September; and Q4 = October–December) and semesters (S1 = January–June and S2 = July–December) from the start of the selection year. Birthdates were analyzed for: (a) each playing level and (b) each age group irrespective of playing level. For the varied playing levels examined, an RAE was evident in “Development” and “Performance” playing levels only at youth level. When examining each age group, an RAE was observed in U12–U17 players only. While there was a slight asymmetry favoring Q1 born senior professional players, the RAE was not present within this group of our sample. Results from our study suggest that a bias in selecting individuals born earlier in the selection year may exist within male soccer academy structures, but not at amateur level. The asymmetry favoring chronologically older players at youth but not professional level questions the efficacy of this (un)conscious bias within male Scottish soccer players.
Maintenance Therapy in AML

Recent advances in therapeutics coupled with steady improvements in supportive care for patients with acute myeloid leukemia (AML) have led to improved outcomes. Despite these advances, even in patients that achieve a complete remission with initial therapy high rates of relapse remain a clinical dilemma. For decades, investigators have attempted strategies of maintenance therapy to prolong both remission duration and overall survival in patients with AML. These approaches have included cytotoxic chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecule therapy. Overall, the evidence in favor of maintenance therapy is limited. Recent strategies, especially with hypomethylating agents have begun to show promise as maintenance therapy in improving clinical outcomes. Ongoing and future studies will continue to elucidate the true role for maintenance therapy options in patients with AML. In this review we summarize prior and ongoing maintenance therapy approaches in AML and highlight some of the most promising strategies.
Development and Validation of a Machine Learning Prognostic Model for Hepatocellular Carcinoma Recurrence After Surgical Resection

Surgical resection remains primary curative treatment for patients with hepatocellular carcinoma (HCC) while over 50% of patients experience recurrence, which calls for individualized recurrence prediction and early surveillance. This study aimed to develop a machine learning prognostic model to identify high-risk patients after surgical resection and to review importance of variables in different time intervals. The patients in this study were from two centers including Eastern Hepatobiliary Surgery Hospital (EHSH) and Mengchao Hepatobiliary Hospital (MHH). The best-performed model was determined, validated, and applied to each time interval (0–1 year, 1–2 years, 2–3 years, and 3–5 years). Importance scores were used to illustrate feature importance in different time intervals. In addition, a risk heat map was constructed which visually depicted the risk of recurrence in different years. A total of 7,919 patients from two centers were included, of which 3,359 and 230 patients experienced recurrence, metastasis or died during the follow-up time in the EHSH and MHH datasets, respectively. The XGBoost model achieved the best discrimination with a c-index of 0.713 in internal validation cohort. Kaplan-Meier curves succeed to stratify external validation cohort into different risk groups (p < 0.05 in all comparisons). Tumor characteristics contribute more to HCC relapse in 0 to 1 year while HBV infection and smoking affect patients’ outcome largely in 3 to 5 years. Based on machine learning prediction model, the peak of recurrence can be predicted for individual HCC patients. Therefore, clinicians can apply it to personalize the management of postoperative survival.
Integrative Metagenomics–Metabolomics for Analyzing the Relationship Between Microorganisms and Non-volatile Profiles of Traditional Xiaoqu

Xiaoqu, one of three traditional jiuqu in China, is a saccharifying and fermenting agent used in Xiaoqu jiu brewing, with different ingredient compositions and preparation techniques used in various regions. The yield and quality of Xiaoqu jiu are significantly affected by the metabolites and microbiota of Xiaoqu; however, the associated relationship remains poorly understood. This study aimed to analyze this relationship in three typical traditional Xiaoqu from the Guizhou province in China. The non-volatile metabolites of Xiaoqu were detected using gas chromatography time-of-flight mass spectrometry, whereas the classification and metabolic potential of the microbiota were investigated using metagenomic sequencing. Results show that Firmicutes, Proteobacteria, and Actinobacteria represent the dominant bacterial phyla, with Lactobacillus, Bacillus, Acinetobacter, Leuconostoc, and Weissella found to be the dominant bacterial genera. Meanwhile, Ascomycota, Mucoromycota, and Basidiomycota are the dominant fungal phyla with Aspergillus, Saccharomyces, Pichia, Rhizopus, and Phycomyces being the predominant fungal genera. Functional annotation of the microbiota revealed a major association with metabolism of carbohydrates, cofactors, and vitamins, as well as amino acids. A total of 39 significantly different metabolites (SDMs) were identified that are involved in 47 metabolic pathways, primarily that of starch and sucrose; glycine, serine, and threonine; glyoxylate and dicarboxylate; pyruvate; as well as biosynthesis of pantothenate and CoA. Further, based on Spearman's correlation analysis, Aspergillus, Saccharomyces, Lactobacillus, Acetobacter, Weissella, Pantoea, Desmospora, and Bacillus are closely correlated with production of physicochemical indexes and SDMs. Moreover, the metabolic network generated for the breakdown of substrates and formation of SDMs in Xiaoqu was found to primarily center on the metabolism of carbohydrates and the tricarboxylic acid cycle. These results provide insights into the functional microorganisms and metabolic patterns present in traditional Guizhou Xiaoqu and might guide researchers in the production of stable and efficient Xiaoqu in the future.
Determinants of Neural Plastic Changes Induced by Motor Practice

Short-term motor practice leads to plasticity in the primary motor cortex (M1). The purpose of this study is to investigate the factors that determine the increase in corticospinal tract (CST) excitability after motor practice, with special focus on two factors; “the level of muscle activity” and “the presence/absence of a goal of keeping the activity level constant. ” Fifteen healthy subjects performed four types of rapid thumb adduction in separate sessions. In the “comfortable task” (C) and “forceful task” (F), the subjects adducted their thumb using comfortable and strong forces. In the “comfortable with a goal task” (CG) and “forceful with a goal task” (FG), subjects controlled the muscle activity at the same level as in the C and F, respectively, by adjusting the peak electromyographic amplitude within the target ranges. Paired associative stimulation (PAS), which combines peripheral nerve (median nerve) stimulation and transcranial magnetic stimulation (TMS), with an inter-stimulus interval of 25 ms (PAS25) was also done. Before and after the motor tasks and PAS25, TMS was applied to the M1. None of the four tasks showed any temporary changes in behavior, meaning no learning occurred. Motor-evoked potential (MEP) amplitude increased only after the FG and it exhibited a positive correlation with the MEP increase after PAS25, suggesting that FG and PAS25 share at least similar plasticity mechanisms in the M1. Resting motor threshold (RMT) decreased only after FG, suggesting that FG would also be associated with the membrane depolarization of M1 neurons. These results suggest task-dependent plasticity from the synergistic effect of forceful muscle activity and of setting a goal of keeping the activity level constant.
Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/β-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/β-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.