Miracle-dz/UniFAR-FTUs huggingface dataset:
Predicting the Outcome of Voriconazole Individualized Medication Using Integrated Pharmacokinetic/Pharmacodynamic Model

Therapeutic drug monitoring is considered to be an effective tool for the individualized use of voriconazole. However, drug concentration measurement alone doesn’t take into account the susceptibility of the infecting microorganisms to the drug. Linking pharmacodynamic data with the pharmacokinetic profile of individuals is expected to be an effective method to predict the probability of a certain therapeutic outcome. The objective of this study was to individualize voriconazole regimens by integrating individual pharmacokinetic parameters and pathogen susceptibility data through Monte Carlo simulations The individual pharmacokinetic parameters of 35 hospitalized patients who received voriconazole were calculated based on a validated population pharmacokinetic model. The area under the concentration-time curve for free drug/minimal inhibitory concentration (fAUCss/MIC) > 25 was selected as the pharmacokinetic/pharmacodynamic (PK/PD) parameter predicting the efficacy of voriconazole. The cumulative fraction of response (CFR) of the target value was assessed. To verify this conclusion, a logistic regression analysis was used to explore the relationship between actual clinical efficiency and the CFR value. For the 35 patients, the area under the free drug concentration-time curve (fAUCss) was calculated to be 34.90 ± 21.67 mgh/L. According to the dualistic logistic regression analysis, the minimal inhibitory concentration (MIC) value of different kinds of fungi had a great influence on the effectiveness of clinical treatment. It also showed that the actual clinical efficacy and the CFR value of fAUCss/MIC had a high degree of consistency. The results suggest that it is feasible to individualize voriconazole dosing and predict clinical outcomes through the integration of data on pharmacokinetics and antifungal susceptibility.
Can the Cytokine Profile According to ABO Blood Groups Be Related to Worse Outcome in COVID-19 Patients? Yes, They Can

Severe status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.
Effect of Immune Checkpoint Blockade on Myeloid-Derived Suppressor Cell Populations in Patients With Melanoma

Introduction Myeloid-derived suppressor cells (MDSC) are a subset of immature myeloid cells that inhibit anti-tumor immunity and contribute to immune therapy resistance. MDSC populations were measured in melanoma patients receiving immune checkpoint inhibitors (ICI). Methods Patients with melanoma (n=128) provided blood samples at baseline (BL), and before cycles 2 and 3 (BC2, BC3). Peripheral blood mononuclear cells (PBMC) were analyzed for MDSC (CD33+/CD11b+/HLA- DRlo/-) and MDSC subsets, monocytic (CD14+, M-MDSC), granulocytic (CD15+, PMN-MDSC), and early (CD14-/CD15-, E-MDSC) via flow cytometry. Statistical analysis employed unpaired and paired t-tests across and within patient cohorts. Results Levels of MDSC as a percentage of PBMC increased during ICI (BL: 9.2 ± 1.0% to BC3: 23.6 ± 1.9%, p<0.0001), and patients who developed progressive disease (PD) had higher baseline MDSC. In patients who had a complete or partial response (CR, PR), total MDSC levels rose dramatically and plateaued (BL: 6.4 ± 1.4%, BC2: 26.2 ± 4.2%, BC3: 27.5 ± 4.4%; p<0.0001), whereas MDSC rose less sharply in PD patients (BL: 11.7 ± 2.1%, BC2: 18.3 ± 3.1%, BC3: 19.0 ± 3.2%; p=0.1952). Subset analysis showed that within the expanding MDSC population, PMN-MDSC and E-MDSC levels decreased, while the proportion of M-MDSC remained constant during ICI. In PD patients, the proportion of PMN-MDSC (as a percentage of total MDSC) decreased (BL: 25.1 ± 4.7%, BC2: 16.1 ± 5.2%, BC3: 8.6 ± 1.8%; p=0.0105), whereas a heretofore under-characterized CD14+/CD15+ double positive MDSC subpopulation increased significantly (BL: 8.7 ± 1.4% to BC3: 26.9 ± 4.9%; p=0.0425). Conclusions MDSC levels initially increased significantly in responders. PMN-MDSC decreased and CD14+CD15+ MDSC increased significantly in PD patients. Changes in MDSC levels may have prognostic value in ICI.
The Mucosal and Serological Immune Responses to the Novel Coronavirus (SARS-CoV-2) Vaccines

Background Although the serological antibody responses induced by SARS-CoV-2 vaccines are well characterized, little is known about their ability to elicit mucosal immunity. Objectives This study aims to examine and compare the mucosal and systemic responses of recipients of two different vaccination platforms: mRNA (Comirnaty) and inactivated virus (CoronaVac). Methods Serial blood and nasal epithelial lining fluid (NELF) samples were collected from the recipients of either Comirnaty or CoronaVac. The plasma and NELF immunoglobulins A and G (IgA and IgG) specific to SARS-CoV-2 S1 protein (S1) and their neutralization effects were quantified. Results Comirnaty induced nasal S1-specific immunoglobulin responses, which were evident as early as 14 ± 2 days after the first dose. In 64% of the subjects, the neutralizing effects of NELF persisted for at least 50 days. Moreover, 85% of Comirnaty recipients exhibited S1-specific IgA and IgG responses in plasma by 14 ± 2 days after the first dose. By 7 ± 2 days after the booster, all plasma samples possessed S1-specific IgA and IgG responses and were neutralizing. The induction of S1-specific plasma antibodies by CoronaVac was IgG dominant, and 83% of the subjects possessed S1-specific IgG by 7 ± 2 days after the booster, with neutralizing effects. Conclusion Comirnaty induces S1-specific IgA and IgG responses with neutralizing activity in the nasal mucosa; a similar response is not seen with CoronaVac. Clinical Implication The presence of a nasal response with mRNA vaccine may provide additional protection compared with inactivated virus vaccine. However, whether such widespread immunological response may produce inadvertent adverse effects in other tissues warrants further investigation.
A Mediating Model of Emotional Balance and Procrastination on Academic Performance

Deficit in the management of time continues to be an important difficulty students are faced with. The present work aimed to test the hypothesis that self-regulation is the major predictor of academic performance and that this effect can be mediated both by the student’s emotional regulation and his propensity for procrastination. Participants were 450 university students who were administered MPP and AIP. The procedures involved the administration of instruments and the collection of average exam grades as a measure of academic performance. The effect of a specific component of self-regulation on academic performance, namely action orientation, was significant, while procrastination showed a limiting effect on the performative quality of the student. The model confirmed the mediation role of emotional balance on the effect that action orientation exerts on procrastination, and the mediation of procrastination in the relationship between action orientation and Academic Performance. Results of the study suggest focusing on student support and on prevention of procrastinating behavior through programs that enhance first of all student’s proactive attitude, planning skills, self-monitoring and effective/efficient time management, and secondly, emotional awareness and regulation of emotional response in situations of stress and performance anxiety.
MiR-27a-3p Promotes Non-Small Cell Lung Cancer Through SLC7A11-Mediated-Ferroptosis

Background Ferroptosis is a newly generated regulatory cell death promoted by the accumulated lipid-based reactive oxygen species (ROS). Solute carrier family 7 member 11 (SLC7A11), the cystine/glutamate antiporter, is known as a ferroptosis executor that exhibits a positive correlation with carcinoma progression because of antioxidant function. Nonetheless, it is yet unclear on the understanding of ferroptosis regulation in lung cancer. Methods Database, qRT-PCR, Western-blot (WB), and immunohistochemistry were utilized to determine SLC7A11 expression and function, as well as gene iron related to necrosis in clinical tissue specimens and cells; a ferroptosis inducer, inhibitors, and SLC7A11 lentivirus were used to confirm SLC7A11’s biological activity in cell viability, oxidative stress, lipid peroxidation, and iron ion enrichment in non-small cell lung cancer (NSCLC) in different cells; lentivirus was used to infect lung adenocarcinoma cell lines to acquire miR-27a-3p overexpression and knockdown cell lines, and to detect SLC7A11 level through qRT-PCR and WB. The influence of upregulated/downregulated miR-27a-3p on ferroptosis and other related biological characteristics of lung adenocarcinoma cell lines was detected. Results Upregulated SLC7A11 was shown in NSCLC patients and cells, and increased SLC7A11 had a relation to the poorly prognostic status of NSCLC patients. Besides, a novel miRNA, miR-27a-3p, was an essential modulator of ferroptosis via directly targeting SLC7A11 in NSCLC cells. Overexpressing miR-27a-3p led to SLC7A11 suppression via directly binding to its 3’-UTR, followed by the reduction of erastin-caused ferroptosis. In contrast, inhibited miR-27a-3p resulted in an increase in NSCLC cells’ sensitivity to erastin. Of importance, the accumulated lipid ROS and cell death of iron peptide mediated by anti-miR-27a-3p can be eliminated by impeding the glutamylation process. Our literature collectively uncovered that miR-27a-3p modulated ferroptosis by targeting SLC7A11 in NSCLC cells, illustrating the important role of miRNA in ferroptosis. Conclusion MiR-27a-3p modulates ferroptosis via targeting SLC7A11 in NSCLC cells, implying the significant role of miR-27a-3p/SLC7A11 in ferroptosis.
Radiomics Based on Contrast-Enhanced MRI in Differentiation Between Fat-Poor Angiomyolipoma and Hepatocellular Carcinoma in Noncirrhotic Liver: A Multicenter Analysis

Objective This study aims to develop and externally validate a contrast-enhanced magnetic resonance imaging (CE-MRI) radiomics-based model for preoperative differentiation between fat-poor angiomyolipoma (fp-AML) and hepatocellular carcinoma (HCC) in patients with noncirrhotic livers and to compare the diagnostic performance with that of two radiologists. Methods This retrospective study was performed with 165 patients with noncirrhotic livers from three medical centers. The dataset was divided into a training cohort (n = 99), a time-independent internal validation cohort (n = 24) from one center, and an external validation cohort (n = 42) from the remaining two centers. The volumes of interest were contoured on the arterial phase (AP) images and then registered to the venous phase (VP) and delayed phase (DP), and a total of 3,396 radiomics features were extracted from the three phases. After the joint mutual information maximization feature selection procedure, four radiomics logistic regression classifiers, including the AP model, VP model, DP model, and combined model, were built. The area under the receiver operating characteristic curve (AUC), diagnostic accuracy, sensitivity, and specificity of each radiomics model and those of two radiologists were evaluated and compared. Results The AUCs of the combined model reached 0.789 (95%CI, 0.579–0.999) in the internal validation cohort and 0.730 (95%CI, 0.563–0.896) in the external validation cohort, higher than the AP model (AUCs, 0.711 and 0.638) and significantly higher than the VP model (AUCs, 0.594 and 0.610) and the DP model (AUCs, 0.547 and 0.538). The diagnostic accuracy, sensitivity, and specificity of the combined model were 0.708, 0.625, and 0.750 in the internal validation cohort and 0.619, 0.786, and 0.536 in the external validation cohort, respectively. The AUCs for the two radiologists were 0.656 and 0.594 in the internal validation cohort and 0.643 and 0.500 in the external validation cohort. The AUCs of the combined model surpassed those of the two radiologists and were significantly higher than that of the junior one in both validation cohorts. Conclusions The proposed radiomics model based on triple-phase CE-MRI images was proven to be useful for differentiating between fp-AML and HCC and yielded comparable or better performance than two radiologists in different centers, with different scanners and different scanning parameters.
Adding Pay-for-Performance Program to Routine Care Was Related to a Lower Risk of Depression Among Type 2 Diabetes Patients in Taiwan

Background: Patients with type 2 diabetes (T2DM) often experience depression during treatment, negatively influencing their treatment compliance and clinical outcomes. Recently, the pay-for-performance (P4P) program for chronic diseases, with high-cost and high-risk feature, such as T2DM, has been implemented and has been operational for several years. Nevertheless, its effect on the risk of developing depression among T2DM cases is unknown. This study aims to explore the association of P4P use with the subsequent risk of developing depression among these patients. Methods: This cohort study used a nationwide health insurance database to identify patients 20–70 years of age newly diagnosed with T2DM who enrolled in the P4P program between 2001 and 2010. From this group, we enrolled 17,022 P4P users and then 17,022 non-P4P users who were randomly selected using propensity-score–matching. Enrolled patients were followed until the end of 2012 to record the occurrence of depression. The Cox proportional hazards regression was utilized to obtain the adjusted hazard ratio (aHR) for P4P use. Results: During the study period, a total of 588 P4P users and 1,075 non-P4P users developed depression at incidence rates of 5.89 and 8.41 per 1,000 person-years, respectively. P4P users had a lower depression risk than did non-P4P users (aHR, 0.73; 95% Confidence Interval, 0.65–0.80). This positive effect was particularly prominent in those receiving high-intensity use of the P4P program. Conclusion: Integrating P4P into routine care for patients with T2DM may have beneficial effects on curtailing the subsequent risk of depression.
A Population of M2 Macrophages Associated With Bone Formation

We previously identified transient brown adipocyte-like cells associated with heterotopic ossification (HO). These ancillary cells support new vessel synthesis essential to bone formation. Recent studies have shown that the M2 macrophage contributes to tissue regeneration in a similar way. To further define the phenotype of these brown adipocyte-like cells they were isolated and characterized by single-cell RNAseq (scRNAseq). Analysis of the transcriptome and the presence of surface markers specific for macrophages suggest that these cells are M2 macrophages. To validate these findings, clodronate liposomes were delivered to the tissues during HO, and the results showed both a significant reduction in these macrophages as well as bone formation. These cells were isolated and shown in culture to polarize towards either M1 or M2 similar to other macrophages. To confirm that these are M2 macrophages, mice received lipopolysacheride (LPS), which induces proinflammation and M1 macrophages. The results showed a significant decrease in this specific population and bone formation, suggesting an essential role for M2 macrophages in the production of bone. To determine if these macrophages are specific to HO, we isolated these cells using fluorescence-activated cell sorting (FACS) from a bone defect model and subjected them to scRNAseq. Surprisingly, the macrophage populations overlapped between the two groups (HO-derived versus callus) suggesting that they may be essential ancillary cells for bone formation in general and not selective to HO. Of further note, their unique metabolism and lipogenic properties suggest the potential for unique cross talk between these cells and the newly forming bone.
Single-Trial EEG Classification via Orthogonal Wavelet Decomposition-Based Feature Extraction

Achieving high classification performance is challenging due to non-stationarity and low signal-to-noise ratio (low SNR) characteristics of EEG signals. Spatial filtering is commonly used to improve the SNR yet the individual differences in the underlying temporal or frequency information is often ignored. This paper investigates motor imagery signals via orthogonal wavelet decomposition, by which the raw signals are decomposed into multiple unrelated sub-band components. Furthermore, channel-wise spectral filtering via weighting the sub-band components are implemented jointly with spatial filtering to improve the discriminability of EEG signals, with an l2-norm regularization term embedded in the objective function to address the underlying over-fitting issue. Finally, sparse Bayesian learning with Gaussian prior is applied to the extracted power features, yielding an RVM classifier. The classification performance of SEOWADE is significantly better than those of several competing algorithms (CSP, FBCSP, CSSP, CSSSP, and shallow ConvNet). Moreover, scalp weight maps of the spatial filters optimized by SEOWADE are more neurophysiologically meaningful. In summary, these results demonstrate the effectiveness of SEOWADE in extracting relevant spatio-temporal information for single-trial EEG classification.
The Glucocorticoid Receptor Polymorphism Landscape in Patients With Diamond Blackfan Anemia Reveals an Association Between Two Clinically Relevant Single Nucleotide Polymorphisms and Time to Diagnosis

NR3C1, the gene encoding the glucocorticoid receptor, is polymorphic presenting numerous single nucleotide polymorphisms (SNPs) some of which are emerging as leading cause in the variability of manifestation and/or response to glucocorticoids in human diseases. Since 60–80% of patients with Diamond Blackfan anemia (DBA), an inherited pure red cell aplasia induced by mutations in ribosomal protein genes became transfusion independent upon treatment with glucocorticoids, we investigated whether clinically relevant NR3C1 SNPs are associated with disease manifestation in DBA. The eight SNPs rs10482605, rs10482616, rs7701443, rs6189/rs6190, rs860457, rs6198, rs6196, and rs33388/rs33389 were investigated in a cohort of 91 European DBA patients. Results were compared with those observed in healthy volunteers (n=37) or present in public genome databases of Italian and European populations. Although, cases vs. control analyses suggest that the frequency of some of the minor alleles is significantly altered in DBA patients with respect to healthy controls or to the Italian or other European registries, lack of consistency among the associations across different sets suggests that overall the frequency of these SNPs in DBA is not different from that of the general population. Demographic data (47 females and 31 males) and driver mutations (44 S and 29 L genes and eight no-known mutation) are known for 81 patients while glucocorticoid response is known, respectively, for 81 (36 responsive and 45 non-responsive) and age of disease onsets for 79 (55 before and 24 after 4months of age) patients. Neither gender nor leading mutations were associated with the minor alleles or with disease manifestation. In addition, none of the SNPs met the threshold in the response vs. non-responsive groups. However, two SNPs (rs6196 and rs860457) were enriched in patients manifesting the disease before 4months of age. Although the exact biomechanistical consequences of these SNPs are unknown, the fact that their configuration is consistent with that of regulatory regions suggests that they regulate changes in glucocorticoid response during ontogeny. This hypothesis was supported by phosphoproteomic profiling of erythroid cells expanded ex vivo indicating that glucocorticoids activate a ribosomal signature in cells from cord blood but not in those from adult blood, possibly providing a compensatory mechanism to the driving mutations observed in DBA before birth.
Peritumoral Brain Edema in Metastases May Be Related to Glymphatic Dysfunction

Objectives The proliferation of microvessels with increased permeability is thought to be the cause of peritumoral brain edema (PTBE) in metastases. The contribution of the glymphatic system to the formation of PTBE in brain metastases remains unexplored. We aimed to investigate if the PTBE volume of brain metastases is related to glymphatic dysfunction. Materials and Methods A total of 56 patients with brain metastases who had preoperative dynamic susceptibility contrast-enhanced perfusion-weighted imaging for calculation of tumor cerebral blood volume (CBV) and diffusion tensor imaging for calculations of tumor apparent diffusion coefficient (ADC), tumor fractional anisotropy (FA), and analysis along perivascular space (ALPS) index were analyzed. The volumes of PTBE, whole tumor, enhancing tumor, and necrotic and hemorrhagic portions were manually measured. Additional information collected for each patient included age, sex, primary cancer, metastasis location and number, and the presence of concurrent infratentorial tumors. Linear regression analyses were performed to identify factors associated with PTBE volume. Results Among 56 patients, 45 had solitary metastasis, 24 had right cerebral metastasis, 21 had left cerebral metastasis, 11 had bilateral cerebral metastases, and 11 had concurrent infratentorial metastases. On univariable linear regression analysis, PTBE volume correlated with whole tumor volume (β = -0.348, P = 0.009), hemorrhagic portion volume (β = -0.327, P = 0.014), tumor ADC (β = 0.530, P <.001), and ALPS index (β = -0.750, P <.001). The associations of PTBE volume with age, sex, tumor location, number of tumors, concurrent infratentorial tumor, enhancing tumor volume, necrotic portion volume, tumor FA, and tumor CBV were not significant. On multivariable linear regression analysis, tumor ADC (β = 0.303; P = 0.004) and ALPS index (β = -0.624; P < 0.001) were the two independent factors associated with PTBE volume. Conclusion Metastases with higher tumor ADC and lower ALPS index were associated with larger peritumoral brain edema volumes. The higher tumor ADC may be related to increased periarterial water influx into the tumor interstitium, while the lower ALPS index may indicate insufficient fluid clearance. The changes in both tumor ADC and ALPS index may imply glymphatic dysfunction, which is, at least, partially responsible for peritumoral brain edema formation.