Miracle-dz/UniFAR-FTUs huggingface dataset:
Seroprevalence of Dengue, Chikungunya and Zika at the epicenter of the congenital microcephaly epidemic in Northeast Brazil: A population-based survey

Background The Dengue viruses (DENV) serotypes 1, 2, 3 and 4 were re-introduced in the Northeast Brazil from the 1980s until 2010s. Zika (ZIKV) and Chikungunya (CHIKV) viruses were introduced around 2014 and caused large outbreaks in 2015 and 2016. However, the true extent of the ZIKV and CHIKV outbreaks and the risk factors associated with exposure remain vague. Methods We conducted a stratified multistage household serosurvey among residents aged between 5 and 65 years in the city of Recife, Northeastern Brazil, from August 2018 to February 2019. The city neighborhoods were stratified according to high, intermediate, and low socioeconomic strata (SES). Previous ZIKV, DENV and CHIKV infections were detected by IgG based enzyme linked immunosorbent assays (ELISA) . Recent ZIKV and CHIKV infections were assessed through IgG3 and IgM ELISA, respectively. Design-adjusted seroprevalence were estimated by age group, sex, and SES. The ZIKV seroprevalence was adjusted to account for the cross-reactivity with dengue. Individual and household-related risk factors were analyzed through regression models to calculate the force of infection. Odds Ratio (OR) were estimated as measure of effect. Principal findings A total of 2,070 residents were investigated. The forces of infection for high SES were lower for all three viruses as compared to low SES. Overall, DENV seroprevalence was 88.7% (CI95%:87.0-90.4), (81.2% (CI95%:76.9-85.6) in the high SES and 90.7% (CI95%:88.3-93.2) in the low). The overall adjusted ZIKV seroprevalence was 34.6% (CI95%:20.0-50.9), (47.4% (CI95%:31.8-61.5) in the low SES and 23.4% (CI95%:12.2-33.8) in the high). CHIKV seroprevalence was 35.7% (CI95%:32.6-38.9), (38.6% (CI95%:33.6-43.6) in the low SES and 22.3% (CI95%:15.8-28.8) in the high). ZIKV seroprevalence increased with age while CHIKV seroprevalence was almost constant through age. The serological markers of recent infections for ZIKV and CHIKV were 1.5% (CI95%:0.1-3.7) and 3.5% (CI95%:2.7-4.2) respectively. Conclusions Our results confirmed continued DENV transmission and intense ZIKV and CHIKV transmission during the 2015/2016 epidemics followed by ongoing low-level transmission. The study also highlights that a significant proportion of the population is likely still susceptible to be infected by ZIKV and CHIKV, raising questions on herd immunity and antibody detection thresholds and the reasons underlying cease of the ZIKV epidemic in 2017/18.
Early EEG biomarkers of perinatal arterial ischemic stroke: a case series

Background: Continuous electroencephalogram (EEG) monitoring after seizures may provide an early clue to the diagnosis of perinatal arterial ischemic stroke (PAIS). We aimed to explore EEG biomarkers and seizure patterns of PAIS within 7 days. Methods: Data of children with PAIS were retrospectively analyzed. Using multi-channel video electroencephalogram (vEEG) and amplitude-integrated electroencephalogram (aEEG), the patients were divided into three groups according to the monitoring start time after symptom onset: [≤]48 h, 48-72 h, and 4-7 days. The characteristics of EEG activity and the law of seizures were compared across groups. Together with magnetic resonance imaging (MRI), the spatial correspondence between brain electrical activity and injury site was determined. Results: Of 21 children studied, 19 (90.47%) developed disease within 48 h of delivery. Abnormal sleep-wake cycle, abnormal fast-wave activity, abnormal wave activity, hemispheric asymmetry, electrographic seizures (ESz), and electroclinical seizures (ECSz) were more common in the [≤]48 h group and 48-72 h group. Differences among all groups were statistically significant (P <0.01). The most common abnormal wave activity was sharp wave or freak wave, consistent with the MRI-confirmed injury site. ESz and ECSz were detected in 12 cases (92.31%) in the [≤]48 h group and two cases (15.38%) in the 48-72 h group, 66.67% were clonic, and 91.67% were frequent seizures. ESz or ECSz were not detected in the 4-7-day group. The starting point of ESz or ECSz was consistent with the area of the lesion shown by MRI. Conclusions: Bi-hemispheric diffuse abnormal fast wave activity, sharp wave or freak wave activity in the local brain region, and ESz or ECSz initiated in the same brain region are EEG biomarkers indicating PAIS. The duration of ESz or ECSz triggered by PAIS was less than 72 h.
The Singapore Experience With Uncontrolled Gout: Unmet Needs in the Management of Patients

Gout is the most common type of inflammatory arthritis, and its impact on cardiovascular health and quality of life is often underestimated. The prevalence and incidence of gout are increasing globally. Further, ischemic heart disease (IHD) and chronic kidney disease (CKD) are prevalent in gout patients. Some unmet needs for gout management include physicians' low initiation rate of urate-lowering therapy (ULT) and poor treatment adherence in patients with gout. There is also a lack of randomized controlled trials that establish safe doses of acute and long-term treatment for gout, particularly in patients with IHD and stage 4 CKD and above (including end-stage renal failure). Furthermore, there is also a lack of studies showing optimal serum uric acid (SUA) target and validated clinical outcome measures, including disease activity and remission criteria for gout tailored to treat-to-target approaches and the high cost of newer gout medications. The causal relationship between asymptomatic hyperuricemia or gout with comorbidities such as IHD and CKD has yet to be fully elucidated. There is a pressing need for collaborative international efforts to address the overall suboptimal management of gout.
Fast computation of tagged MRI motion fields with subspace approximation techniques

MRI tagging is a technique for measuring heart deformations. In tagged MR images, a set of dark lines are encoded within the deforming Left-Ventricle (LV) tissue for quantitative measurement of motion. The points along tag lines measured at different frames and different directions carry important information for measuring the 3D motion of LV. However, these measurements are sparse and therefore multidimensional interpolation techniques are needed to reconstruct a dense displacement field. Here, a novel spline technique is used to accomplish this task. The authors formulate the displacement estimation as a variational problem and then use B-spline bases to approximate the solution. Efficient numerical methods are derived by taking advantages of B-spline properties. The proposed techniques can improve the results significantly with respect to computational time as well as the computational accuracy. The new methods have been validated on both simulated and in-vivo heart data.
Isolation and Characterization of trans‐p‐Hydroxycinnamoyl Meroterpenoids from Ganoderma sinensis

Zizhines V, W, Y, Z, (±)‐zizhines X, and Z1−Z3, and (±)‐ganosinensol L, thirteen new compounds including four pairs of enantiomers and a known compound (−)‐ganosinensol L, were isolated from the fruiting bodies of Ganoderma sinensis. Their structures were identified by spectroscopic, computational methods, and CD (circular dichroism spectroscopy) comparisons. Zizhines V−Z and Z1−Z3 are meroterpenoids consisting of the phenolic and the terpenoidal parts. All the compounds except zizhine Z3 bear a common trans‐p‐hydroxycinnamoyl group. Biological evaluation shows that (−)‐zizhine Z1 inhibits cell migration in the MDA‐MB‐231 cell lines. The present study discloses the chemical profiling of G. sinensis and paves the way for its development as functional products to benefit chronic disorders.
Interferon‐inducible phospholipids govern IFITM3‐dependent endosomal antiviral immunity

The interferon‐induced transmembrane proteins (IFITM) are implicated in several biological processes, including antiviral defense, but their modes of action remain debated. Here, taking advantage of pseudotyped viral entry assays and replicating viruses, we uncover the requirement of host co‐factors for endosomal antiviral inhibition through high‐throughput proteomics and lipidomics in cellular models of IFITM restriction. Unlike plasma membrane (PM)‐localized IFITM restriction that targets infectious SARS‐CoV2 and other PM‐fusing viral envelopes, inhibition of endosomal viral entry depends on lysines within the conserved IFITM intracellular loop. These residues recruit Phosphatidylinositol 3,4,5‐trisphosphate (PIP3) that we show here to be required for endosomal IFITM activity. We identify PIP3 as an interferon‐inducible phospholipid that acts as a rheostat for endosomal antiviral immunity. PIP3 levels correlated with the potency of endosomal IFITM restriction and exogenous PIP3 enhanced inhibition of endocytic viruses, including the recent SARS‐CoV2 Omicron variant. Together, our results identify PIP3 as a critical regulator of endosomal IFITM restriction linking it to the Pi3K/Akt/mTORC pathway and elucidate cell‐compartment‐specific antiviral mechanisms with potential relevance for the development of broadly acting antiviral strategies.
Plasma protein-mediated uptake and contradictions to the free drug hypothesis: a critical review

Abstract According to the free drug hypothesis (FDH), only free, unbound drug is available to interact with biological targets. This hypothesis is the fundamental principle that continues to explain the vast majority of all pharmacokinetic and pharmacodynamic processes. Under the FDH, the free drug concentration at the target site is considered the driver of pharmacodynamic activity and pharmacokinetic processes. However, deviations from the FDH are observed in hepatic uptake and clearance predictions, where observed unbound intrinsic hepatic clearance (CLint,u) is larger than expected. Such deviations are commonly observed when plasma proteins are present and form the basis of the so-called plasma protein-mediated uptake effect (PMUE). This review will discuss the basis of plasma protein binding as it pertains to hepatic clearance based on the FDH, as well as several hypotheses that may explain the underlying mechanisms of PMUE. Notably, some, but not all, potential mechanisms remained aligned with the FDH. Finally, we will outline possible experimental strategies to elucidate PMUE mechanisms. Understanding the mechanisms of PMUE and its potential contribution to clearance underprediction is vital to improving the drug development process.
The DNA integrity number and concentration are useful parameters for successful comprehensive genomic profiling test for cancer using formalin‐fixed paraffin embedded tissue

The acquisition of high‐quality biospecimens and the appropriate handling of these materials are indispensable for successful clinical sequencing. We developed a cancer clinical sequencing system targeting 160 cancer genes: PleSSision‐Rapid. Through the PleSSision‐Rapid system, we have analyzed DNA quality evaluated by DIN (DNA integrity number) with 1329 formalin‐fixed paraffin embedded (FFPE) samples including 477 prospectively collected tissues for genomic test (P) and 852 archival samples after routine pathological diagnosis (A1/A2). As a result, the samples with more than DIN 2.1 was 92.0% (439/477) in prospectively collected sample (P), while it was 85.6% (332/388) and 76.7% (356/464) in two types of archival samples (A1/A2). We performed the PleSSision‐Rapid sequence using the samples with over DIN 2.1 and DNA concentration >10 ng/μL with which we were able to construct a DNA library, and the probability of sequence success was almost equivalent during all types of specimen processing, at 90.7% (398/439) in (P), 92.5% (307/332) in (A1) and 90.2% (321/356) in (A2), respectively. Our result indicated the clinical benefit to prepare the prospective collection of FFPE materials for indisputable clinical sequence, and that DIN ≥ 2.1 would be a solid parameter for sample preparation of comprehensive genomic profiling tests.
Deep learning neural network image analysis of immunohistochemical protein expression reveals a significantly reduced expression of biglycan in breast cancer

New breast cancer biomarkers have been sought for better tumor characterization and treatment. Among these putative markers, there is Biglycan (BGN). BGN is a class I small leucine-rich proteoglycan family of proteins characterized by a protein core with leucine-rich repeats. The objective of this study is to compare the protein expression of BGN in breast tissue with and without cancer, using immunohistochemical technique associated with digital histological score (D-HScore) and supervised deep learning neural networks (SDLNN). In this case-control study, 24 formalin–fixed, paraffin-embedded tissues were obtained for analysis. Normal (n = 9) and cancerous (n = 15) tissue sections were analyzed by immunohistochemistry using BGN monoclonal antibody (M01-Abnova) and 3,3’-Diaminobenzidine (DAB) as the chromogen. Photomicrographs of the slides were analysed with D-HScore, using arbitrary DAB units. Another set (n = 129) with higher magnification without ROI selection, was submitted to the inceptionV3 deep neural network image embedding recognition model. Next, supervised neural network analysis, using stratified 20 fold cross validation, with 200 hidden layers, ReLu activation, and regularization at α = 0.0001 were applied for SDLNN. The sample size was calculated for a minimum of 7 cases and 7 controls, having a power = 90%, an α error = 5%, and a standard deviation of 20, to identify a decrease from the average of 40 DAB units (control) to 4 DAB units in cancer. BGN expression in DAB units [median (range)] was 6.2 (0.8 to 12.4) and 27.31 (5.3 to 81.7) in cancer and normal breast tissue, respectively, using D-HScore (p = 0.0017, Mann-Whitney test). SDLNN classification accuracy was 85.3% (110 out of 129; 95%CI = 78.1% to 90.3%). BGN protein expression is reduced in breast cancer tissue, compared to normal tissue.
Parametric population pharmacokinetics of isoniazid: a systematic review

ABSTRACT Introduction Isoniazid (INH) plays an important role in prevention and treatment of tuberculosis (TB). However, large pharmacokinetic (PK) variations are observed in patients receiving standard INH dosages. Considering the influence of PK variations on INH efficacy or adverse reactions, we reviewed the population PK studies of INH and explored significant covariates that influence INH PK. Methods The PubMed and Embase databases were systematically searched from their inception to 30 January 2023. PPK studies on INH using a parametric nonlinear mixed-effect approach were included in this review. The characteristics and identified significant covariates of the included studies were summarized. Results Twenty-one studies conducted in adults, and seven in pediatrics were included. A two-compartment model with first-order absorption and elimination was the frequently used structural model for INH. NAT2 genotype, body size, and age were identified as significant covariates affecting INH PK variation. The median clearance (CL) value in the fast metabolizers was 2.55-fold higher than that in the slow metabolizers. Infants and children had higher CL per weight values than adults with the same metabolic phenotype. In pediatric patients, CL value increased with postnatal age. Conclusions Compared with slow metabolizers, the daily dose of INH should be increased by 200-600 mg in fast metabolizers. To achieve effective treatment, pediatric patients need a higher dose per kilogram than adults. Further PPK studies of anti-tuberculosis drugs are needed to comprehensively understand the covariates that affect their PK characteristics and to achieve accurate dose adjustments.
The effectiveness of neoadjuvant chemoradiotherapy in oesophageal adenocarcinoma with presence of extracellular mucin, signet‐ring cells, and/or poorly cohesive cells

Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet‐ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well‐formed glands), which is a possible confounder. We studied the pre‐ and post‐treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well‐formed glands, extracellular mucin, SRCs, and PCCs were scored in pre‐treatment biopsies and post‐treatment resection specimens. The association between histopathological factors (≥1 and >10%) and tumour regression grade 3–4 (i.e. >10% residual tumour), overall survival, and disease‐free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre‐treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre‐treatment histopathological factors were unrelated to tumour regression grade. Pre‐treatment presence of >10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19–2.53). Patients with post‐treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10–2.99). In conclusion, pre‐treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre‐treatment and any SRCs post‐treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.
HIV-1 DNA and Immune Activation Levels Differ for Long-Lived T-Cells in Lymph Nodes, Compared with Peripheral Blood, during Antiretroviral Therapy

This study provides new insights into the contributions of different CD4+ and CD8+ T-cell subsets to the anatomic differences between LN and blood in individuals with HIV who have optimal versus suboptimal CD4+ T-cell recovery. To our knowledge, this is the first study comparing paired LN and blood CD4+ and CD8+ T-cell differentiation subsets, as well as those subsets in immunological responders versus immunological suboptimal responders. ABSTRACT Elucidating the mechanisms underlying the persistence and location of the HIV reservoir is critical for developing cure interventions. While it has been shown that levels of T-cell activation and the size of the HIV reservoir are greater in rectal tissue and lymph nodes (LN) than in blood, the relative contributions of T-cell subsets to this anatomic difference are unknown. We measured and compared HIV-1 DNA content, expression of the T-cell activation markers CD38 and HLA-DR, and expression of the exhaustion markers programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in naive, central memory (CM), transitional memory (TM), and effector memory (EM) CD4+ and CD8+ T-cells in paired blood and LN samples among 14 people with HIV who were receiving antiretroviral therapy. HIV-1 DNA levels, T-cell immune activation, and TIGIT expression were higher in LN than in blood, especially in CM and TM CD4+ T-cell subsets. Immune activation was significantly higher in all CD8+ T-cell subsets, and memory CD8+ T-cell subsets from LN had higher levels of PD-1 expression, compared with blood, while TIGIT expression levels were significantly lower in TM CD8+ T-cells. The differences seen in CM and TM CD4+ T-cell subsets were more pronounced among participants with CD4+ T-cell counts of <500 cells/μL within 2 years after antiretroviral therapy initiation, thus highlighting increased residual dysregulation in LN as a distinguishing feature of and a potential mechanism for individuals with suboptimal CD4+ T-cell recovery during antiretroviral therapy. IMPORTANCE This study provides new insights into the contributions of different CD4+ and CD8+ T-cell subsets to the anatomic differences between LN and blood in individuals with HIV who have optimal versus suboptimal CD4+ T-cell recovery. To our knowledge, this is the first study comparing paired LN and blood CD4+ and CD8+ T-cell differentiation subsets, as well as those subsets in immunological responders versus immunological suboptimal responders.
Comparison of anterior cervical discectomy and fusion versus anterior cervical corpectomy and fusion in the treatment of localized ossification of the posterior longitudinal ligament

Background The retrospective study was conducted to compare the efficacy of anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) for localized ossification of the posterior longitudinal ligament (OPLL) by evaluating clinical and radiologic outcomes. Methods We reviewed 151 patients to assess the effects of treatment for one or two levels localized OPLL. Perioperative parameters, such as blood loss, operation time and complications, were recorded. Radiologic outcomes, such as the occupying ratio (OR), fusion status, cervical lordosis angle, segmental angle, disc space height, T1 slope, and C2–C7 sagittal vertical axis (SVA), were assessed. Clinical indices, such as the JOA scores and VAS scores, were investigated to compare the two surgical options. Results There were no significant differences in the JOA scores or VAS scores between the two groups (p > 0.05). The operation time, volume of blood loss and incidence of dysphagia were significantly less in the ACDF group than in the ACCF group (p < 0.05). In addition, cervical lordosis, segmental angle and disc space height were significantly different from their preoperative evaluations. No adjacent segment degenerated in the ACDF group. The subsidence rates of implants were 5.2% in the ACDF group and 28.4% in the ACCF group. The degeneration of the ACCF group was 4.1%. The incidence of CSF leaks was 7.8% in the ACDF group and 13.5% in the ACCF group. All the patients ultimately achieved successful fusion. Conclusion Although both options achieved satisfactory primary clinical and radiographic efficacies, ACDF was associated with a shorter surgical procedure, less intraoperative blood loss, better radiologic outcomes, and lower incidence of dysphagia than ACCF.