Miracle-dz/UniFAR-FTUs huggingface dataset:
Direct‐Acting Antivirals and Hepatocellular Carcinoma: No Evidence of Higher Wait‐List Progression or Posttransplant Recurrence

The association between direct‐acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait‐list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait‐list progression and post‐LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait‐list progression adjusted by a propensity score matching (pre‐LT DAA effect) and for post‐LT HCC recurrence (pre‐ or post‐LT DAA effect). From 994 included patients, 50.6% were HCV−, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n = 66) or after LT (n = 98). Patients treated with DAAs before LT presented similar cumulative incidence of wait‐list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P = 0.47) and a similar HCC‐related dropout rate (12.1% [95% CI, 0.4%‐8.1%] versus 12.9% [95% CI, 3.8%‐27.2%]), adjusted for baseline tumor burden, alpha‐fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6‐1.6; P = 0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre‐ or post‐LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%‐4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait‐list tumor progression and HCC recurrence after LT.
Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation

Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno‐occlusive disease (VOD), remains a multi‐organ system complication following haematopoietic cell transplantation (HCT). When SOS/VOD is accompanied by multi‐organ dysfunction, overall mortality rates remain >80%. However, the definitions related to the diagnosis and grading of SOS/VOD after HCT are almost 25 years old and require new and contemporary modifications. Importantly, the pathophysiology of SOS/VOD, including the contribution of dysregulated inflammatory and coagulation cascades as well as the critical importance of liver and vascular derived endothelial dysfunction, have been elucidated. Here we summarise new information on pathogenesis of SOS/VOD; identify modifiable and unmodifiable risk factors for disease development; propose novel, contemporary and panel opinion‐based diagnostic criteria and an innovative organ‐based method of SOS/VOD grading classification; and review current approaches for prophylaxis and treatment of SOS/VOD. This review will hopefully illuminate pathways responsible for drug‐induced liver injury and manifestations of disease, sharpen awareness of risk for disease development and enhance the timely and correct diagnosis of SOS/VOD post‐HCT.
A Multi-level Model to Understand Cervical Cancer Disparities in Appalachia

The Appalachian region experiences higher incidence and mortality due to cervical cancer compared with other regions of the United States. The goal of the Ohio State University Center for Population Health and Health Disparities (CPHHD), called the Community Awareness Resources and Education (CARE) project, was to understand reasons for this disparity. The first wave (2003–2008) of funding included three projects focusing on the known risk factors for cervical cancer, lack of screening, smoking, and infection with human papillomavirus (HPV). On the basis of the results of these projects, the second wave (2011–2017) included four projects, designed to address a multi-level model of factors contributing to cervical disparities in Appalachia. The results of these projects were then used to refine a multi-level model that explains cervical cancer disparities in Appalachia. Future funded projects will take these multi-level explanations for cervical disparities and focus on implementation science strategies to reduce the burden of cervical cancer morbidity and mortality in Appalachia. See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention
Frontline Science: Superior mouse eosinophil depletion in vivo targeting transgenic Siglec‐8 instead of endogenous Siglec‐F: Mechanisms and pitfalls

Eosinophils are important multifunctional granulocytes. When studying eosinophil function and its contribution to diseases, mouse models are often used. Mouse eosinophils selectively express sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐F. Its closest functional paralog on human eosinophils is Siglec‐8. These Siglecs are being used to target eosinophils when exploring their mechanistic roles in disease and for potential therapeutic benefit. In order to facilitate preclinical studies of human Siglec‐8, we developed transgenic mouse strains expressing human Siglec‐8 only on the surface of eosinophils with or without endogenous Siglec‐F and have begun characterizing various cellular functions in vitro and in vivo. Eosinophils from Siglec‐8+ mice, with or without Siglec‐F, responded to Siglec‐8 antibody engagement in vitro by up‐regulating surface CD11b, whereas Siglec‐F antibody had no such effect. Engagement of Siglec‐F or Siglec‐8 with respective antibodies in vitro resulted in only modest increases in cell death. Administration of rat Siglec‐F antibodies to mice led to a significant decrease in Siglec‐F surface expression on eosinophils due to internalization, and thus appeared to decrease eosinophil numbers based on Siglec‐F+ cells, but with proper gaiting strategies did not in fact result in significant eosinophil depletion. In marked contrast, administration of mouse Siglec‐8 antibodies rapidly and effectively depleted eosinophils from blood and spleens of mice, but an F(ab′)2 version did not, indicating an Fc‐mediated mechanism for eosinophil depletion in vivo. Siglec‐8 expressing mice with or without endogenous Siglec‐F will be useful to study Siglec‐8‐based therapeutics, and may be a preferred approach when acute or chronic eosinophil depletion is needed.
Updates in Laboratory Diagnostics for Invasive Fungal Infections

Appropriate diagnosis of invasive fungal infections (IFIs) is critical due to the high rates of morbidity and mortality, as well as the substantial economic burden, associated with the management of these diseases. The recognition of IFI and differentiation from other infections with similar clinical presentations can be challenging, which can lead to diagnostic error that not only has an impact on individual patient health outcomes but also on antimicrobial drug usage and the growing threat of antimicrobial resistance in bacteria. ABSTRACT Appropriate diagnosis of invasive fungal infections (IFIs) is critical due to the high rates of morbidity and mortality, as well as the substantial economic burden, associated with the management of these diseases. The recognition of IFI and differentiation from other infections with similar clinical presentations can be challenging, which can lead to diagnostic error that not only has an impact on individual patient health outcomes but also on antimicrobial drug usage and the growing threat of antimicrobial resistance in bacteria. Therefore, there is a significant need for improved stewardship related to diagnostic testing for and treatment of IFIs. The purpose of this review is to highlight recent advances related to current fungal diagnostics, as well as explore some of the most innovative technology that has emerged with the potential to shift the paradigm of clinical mycology. In general, this review will discuss research related to enhanced fungal culture utilization and identification techniques, expanded applications of fungal antigen testing, and recently developed molecular assays and other novel nonculture fungal diagnostic approaches. Specifically, the application of mass spectrometry, novel glycobiomarker detection, and detection of fungal-specific volatile organic compounds will be reviewed, along with other key updates, to provide the reader with an updated review that extends beyond the basics of IFI laboratory diagnostics. Where appropriate, the reader will be directed to more comprehensive reviews of certain aspects of clinical mycology laboratory testing to provide a broader context for the critical consideration of these updates.
Combined Use of Common Fecal and Blood Markers for Detection of Endoscopically Active Inflammatory Bowel Disease

INTRODUCTION: Monitoring of disease activity is essential in patients with inflammatory bowel disease. Although endoscopic remission is the ideal therapeutic goal, noninvasive biomarkers (blood and fecal) are more acceptable to patients and are less costly. We evaluated the performance of combinations of fecal and blood markers on the detection of endoscopically active disease. METHODS: Patients with ulcerative colitis (UC) or Crohn's disease (CD) on stable medications were recruited. Blood markers included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, platelet count (PLT), and hemoglobin. Fecal biomarkers included fecal calprotectin (FCT) and fecal immunochemical test (FIT). These markers were compared with the endoscopic Mayo score for UC and the Simple Endoscopic Score for CD. RESULTS: One hundred thirteen patients (mean age 44.7 years, 63.7% men, 54.9% patients with UC and 45.1% patients with CD) were recruited. FCT correlated well with FIT (r = 0.58), CRP (r = 0.56), ESR (r = 0.40), albumin (r = −0.54), PLT (r = 0.61), and hemoglobin (r = −0.35; all Ps < 0.001). Among 66 patients with endoscopic evaluation, 39.4% with endoscopically active disease had higher FCT, FIT, CRP, ESR, PLT, lower albumin, and hemoglobin compared with those in endoscopic remission (all Ps < 0.01). All 7 markers demonstrated good area under receiver operating characteristics (>0.7), with FCT being the best (0.91) for endoscopically active disease. Combining FCT and FIT improved the specificity to 95%, but the sensitivity decreased to 65.4%. In the subgroup analysis of UC, adding PLT to FIT improved the sensitivity and specificity to 100% and 90.9%, respectively. DISCUSSION: The combined use of fecal biomarkers and blood indexes is superior to the use of fecal biomarkers alone in identifying endoscopically active disease.
Effectiveness of boosted darunavir plus rilpivirine in patients with long-lasting HIV-1 infection: DARIL study.

BACKGROUND The combination of boosted darunavir plus rilpivirine, once daily, could be a convenient, effective and well-tolerated two-drug regimen to achieve HIV suppression in HIV-infected patients. METHODS Multicentre, retrospective cohort study in nine hospitals in Spain. All HIV-infected subjects starting boosted darunavir plus rilpivirine were included, irrespective of their viral load (VL). The primary objective was the percentage of patients with VL <50 copies/mL at 48 weeks. Secondary objectives included changes in CD4+ cell count, lipid profile and renal function. RESULTS Eighty-one of 84 patients reached Week 48. Fifty-nine (70.2%) patients had VL <50 copies/mL at baseline and the rest had a median VL of 202 (IQR 98-340) copies/mL. Subjects had a median of 21 years of infection with six prior regimens. The main reasons for starting boosted darunavir plus rilpivirine were simplification (44%), kidney or bone toxicity (28.6%) and virological failure (17.9%). Historical genotypes from 47 patients showed 41 (87.2%) patients with NRTI RAMs, 21 (44.7%) with NNRTI RAMs, 12 (25.5%) with primary PI RAMs and 7 (14.9%) with integrase strand transfer inhibitor (INSTI) RAMs. One patient had low-level resistance to boosted darunavir and five patients had some resistance to rilpivirine. At 48 weeks, 71 (87.7%) patients had VL <50 copies/mL. According to undetectable or detectable baseline VL, effectiveness was 91.1% or 80%, respectively. There were four virological failures with no emergence of new RAMs. Three of these patients resuppressed viraemia while maintaining the same regimen. CONCLUSIONS The combination of boosted darunavir plus rilpivirine has shown good effectiveness and tolerability in this cohort of pretreated patients with a long-lasting HIV infection, exposure to multiple antiretroviral regimens and prior HIV resistance.
Ex vivo confocal microscopy: revolution in fast pathology in dermatology

Confocal microscopy with in vivo and ex vivo modalities has been used in the evaluation of skin cancer and other dermatological disorders. Recent developments in ex vivo confocal microscopy allow for faster pathology assessment with greater accuracy by the visualization of cellular and architectural details, similarly to standard pathology, in either paraffin‐embedded or frozen samples. They include the possibility of multimodal confocal microscopy using different lasers and fusion images. New staining protocols including immunostaining, with no damage to conventional histopathology preparation, have been recently described in melanocytic tumours and inflammatory skin diseases. Digital staining with haematoxylin and eosin is also incorporated in the new devices. In this review the applications of ex vivo confocal microscopy will be presented with the description of the technique and the technology, clinical evidence in dermatology and other fields, and further applications.
Hypoxia potentiates the capacity of melanoma cells to evade cisplatin and doxorubicin cytotoxicity via glycolytic shift

The hypoxic environment within solid tumors impedes the efficacy of chemotherapeutic treatments. Here, we demonstrate that hypoxia augments the capacity of melanoma cells to withstand cisplatin and doxorubicin cytotoxicity. We show that B16F10 cells derived from spontaneously formed melanoma and YUMM1.7 cells, engineered to recapitulate human‐relevant melanoma driver mutations, profoundly differ in their vulnerabilities to cisplatin and doxorubicin. The differences are manifested in magnitude of proliferative arrest and cell death rates, extent of mtDNA depletion, and impairment of mitochondrial respiration. In both models, cytotoxicity is mitigated by hypoxia, which augments glycolytic metabolism. Collectively, the findings implicate metabolic reprogramming in drug evasion and suggest that melanoma tumors with distinct genetic makeup may have differential drug vulnerabilities, highlighting the importance of precision anticancer treatments.
Detecting extra-ocular Chlamydia trachomatis in a trachoma-endemic community in Ethiopia: Identifying potential routes of transmission

Background Trachoma elimination efforts are hampered by limited understanding of Chlamydia trachomatis (Ct) transmission routes. Here we aimed to detect Ct DNA at non-ocular sites and on eye-seeking flies. Methods A population-based household survey was conducted in Oromia Region, Ethiopia. Ocular and non-ocular (faces, hands, clothing, water containers and sleeping surfaces) swabs were collected from all individuals. Flies were caught from faces of children. Flies, ocular swabs and non-ocular swabs were tested for Ct by quantitative PCR. Results In total, 1220 individuals in 247 households were assessed. Active trachoma (trachomatous inflammation—follicular) and ocular Ct were detected in 10% and 2% of all-ages, and 21% and 3% of 1–9-year-olds, respectively. Ct was detected in 12% (95% CI:8–15%) of tested non-ocular swabs from ocular-positive households, but in none of the non-ocular swabs from ocular-negative households. Ct was detected on 24% (95% CI:18–32%) of flies from ocular-positive households and 3% (95% CI:1–6%) of flies from ocular-negative households. Conclusion Ct DNA was detected on hands, faces and clothing of individuals living in ocular-positive households suggesting that this might be a route of transmission within Ct infected households. In addition, we detected Ct on flies from ocular-positive households and occasionally in ocular-negative households suggesting that flies might be a vector for transmission within and between Ct infected and uninfected households. These potential transmission routes may need to be simultaneously addressed to suppress transmission.
The beneficial effects of a water-based aerobic exercise session on the blood lipids of women with dyslipidemia are independent of their training status

OBJECTIVES: To evaluate the acute effects of a session of water-based aerobic exercise on the blood lipid levels of women with dyslipidemia and to compare these results according to their training status. METHOD: Fourteen premenopausal women with dyslipidemia, aged 40–50 years, participated in two water-based aerobic exercise sessions, the first when they were generally sedentary and the second after they were trained with a water-based aerobic training program for 12 weeks. Both experimental sessions were performed using the same protocol, lasted 45 min, and incorporated an interval method, alternating 3 min at a rating of perceived exertion (RPE) of 13 and 2 min at an RPE of 9. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein lipase enzyme (LPL) were obtained through venous blood collection before and immediately after each session. A generalized estimating equation method and Bonferroni tests were conducted (with time and training status as factors) for statistical analyses. RESULTS: At enrollment, the mean age of the participants was 46.57 years (95% confidence interval [CI] 44.81−48.34). The statistical analyses showed a significant time effect for all variables (TC: p=0.008; TG: p=0.012; HDL: p<0.001; LPL: p<0.001) except for LDL (p=0.307). However, the training status effect was not significant for any variable (TC: p=0.527; TG: p=0.899; HDL: p=0.938; LDL: p=0.522; LPL: p=0.737). These results indicate that the TC and TG levels reduced and the HDL and LPL concentrations increased from pre- to post-session in similar magnitudes in both sedentary and trained women. CONCLUSIONS: A single water-based aerobic exercise session is sufficient and effective to beneficially modify the lipid profile of women with dyslipidemia, regardless of their training status.
Glycogen synthase kinase 3ß participates in late stages of Dengue virus-2 infection

BACKGROUND Viruses can modulate intracellular signalling pathways to complete their infectious cycle. Among these, the PI3K/Akt pathway allows prolonged survival of infected cells that favours viral replication. GSK3β, a protein kinase downstream of PI3K/Akt, gets inactivated upon activation of the PI3K/Akt pathway, and its association with viral infections has been recently established. In this study, the role of GSK3β during Dengue virus-2 (DENV-2) infection was investigated. METHODS GSK3β participation in the DENV-2 replication process was evaluated with pharmacological and genetic inhibition during early [0-12 h post-infection (hpi)], late (12-24 hpi), and 24 hpi in Huh7 and Vero cells. We assessed the viral and cellular processes by calculating the viral titre in the supernatants, In-Cell Western, western blotting and fluorescence microscopy. RESULTS Phosphorylation of GSK3β-Ser9 was observed at the early stages of infection; neither did treatment with small molecule inhibitors nor pre-treatment prior to viral infection of GSK3β reduce viral titres of the supernatant at these time points. However, a decrease in viral titres was observed in cells infected and treated with the inhibitors much later during viral infection. Consistently, the infected cells at this stage displayed plasma membrane damage. Nonetheless, these effects were not elicited with the use of genetic inhibitors of GSK3β. CONCLUSIONS The results suggest that GSK3β participates at the late stages of the DENV replication cycle, where viral activation may promote apoptosis and release of viral particles.
Continuous renal replacement therapy in elderly with acute kidney injury

The objective of this article is to raise awareness among physicians of the increasing incidence of acute kidney injury in the elderly population and the utility of continuous renal replacement therapy (CRRT) in its management. While CRRT is frequently applied in younger patients, its use in elderly patients is less frequent, for various reasons, including resistance to such an aggressive intervention from the family and the healthcare team. However, predictors of prognosis have been identified and some studies have concluded that advanced age is not associated with poor outcomes. Decisions regarding management are more complex when dealing with the elderly but like very other patient, the approach should be patient-centered.
Executive Dysfunction Related to Binge Drinking in Ischemic Stroke

Background: Recent evidence has shown that cognitive dysfunction is associated with a history of binge drinking in adolescents who do not have an alcohol use disorder. Most previous studies with adults, however, have failed to show a link between cognitive dysfunction and subdiagnostic binge drinking, nor have any studies investigated the additive cognitive effect of binge drinking to ischemic stroke. Objective: To examine whether a pattern of cognitive dysfunction, especially executive and memory dysfunction, in patients with a first-ever ischemic stroke is associated with a history of subdiagnostic binge drinking. Methods: We studied 206 first-ever ischemic stroke patients (18–65 years) and 50 healthy, demographically comparable adults—both groups with no alcohol use disorder. After exclusion by matching, 189 patients and 39 healthy participants were included in our study (228 participants). The binge-drinking group included 76 participants; the non–binge-drinking group included 152. A multivariate analysis of covariance was used to compare nine cognitive functions between the two groups, with age, education, and stroke severity used as covariates. Results: Binge drinking had a significant negative effect on executive functions (P<0.001). The non–binge-drinking group outperformed the binge-drinking group on the Stroop Test (P=0.001), Trail Making Test (P=0.002), and a phonemic fluency test (P=0.005). The Binge×Stroke Severity interaction (P=0.037) indicated that a history of binge drinking increased the negative effect of stroke on executive functions. Conclusions: Subdiagnostic binge drinking may exacerbate the adverse effects of ischemic stroke on executive dysfunction.
Apelin Affects the Progression of Osteoarthritis by Regulating VEGF-Dependent Angiogenesis and miR-150-5p Expression in Human Synovial Fibroblasts

Synovium-induced angiogenesis is central to osteoarthritis (OA) pathogenesis and thus a promising therapeutic target. The adipokine apelin (APLN) is involved in both OA pathogenesis and angiogenesis. We examined the role of APLN in synovium-induced angiogenesis by investigating the crosstalk between APLN and vascular endothelial growth factor (VEGF) expression in human OA synovial fibroblasts (OASFs). We found higher levels of APLN and VEGF expression in OA samples compared with normal samples. APLN-induced stimulation of VEGF expression and VEGF-dependent angiogenesis in OASFs was mitigated by FAK/Src/Akt signaling. APLN also inhibited levels of microRNA-150-5p (miR-150-5p), which represses VEGF production and angiogenesis. Analyses of an OA animal model showed that shAPLN transfection of OASFs rescued pathologic changes in OA cartilage and histology. Here, we found APLN enhances VEGF expression and angiogenesis via FAK/Src/Akt cascade and via downstream suppression of miR-150-5p expression. These findings help to clarify the pathogenesis of adipokine-induced angiogenesis in OA synovium.