Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety, diagnostic accuracy and therapeutic efficacy of digital single-operator cholangioscopy

Background Digital single-operator cholangioscopes (digital SOCs), equipped with an improved image quality, have been recently introduced. Objective The aim of this study is to evaluate the safety and diagnostic and therapeutic efficacy of digital SOCs (Spyglass™ DS). Methods Sixty-seven digital SOC procedures performed between 2015 and 2017 were retrospectively analyzed. Results The most frequent indications for examination were indeterminate biliary strictures (61.2%) and biliary stone disease (23.9%). In 25 patients (37.3), visual findings predicted malignancy with a sensitivity of 88.9%, a specificity of 97.6%, a positive predictive value (PPV) of 96.0% and a negative predictive value (NPV) of 92.9%. For histological analysis, forceps biopsies were performed in 29 patients (43.2%). Compared with visual findings, forceps biopsies yield a lower diagnostic efficacy in diagnosing malignancy (sensitivity 62.5%, specificity 90.0%, PPV 90.9%, NPV 60.0%). Therapeutic interventions were performed in 19 patients with a technical success rate of 89.4%. Adverse events were observed in 17 patients (25.4%). Of these, 11 patients (16.4%) suffered from severe adverse events (pancreatitis, cholangitis or major bleeding), which led to a prolonged hospital stay. Conclusion Digital SOCs have excellent diagnostic and therapeutic efficacies, but are accompanied by high rates of adverse events; therefore, physicians should use digital SOCs in carefully selected cases.
Yellow Flags as Predictors of Rehabilitation Outcome in Chronic Low Back Pain

Objective: While it is agreed that yellow flags (prognostic psychosocial factors for poor recovery in low back pain) predict pain-related outcomes, uncertainty remains regarding which constructs are the central ones, particularly as there is considerable conceptual overlap between constructs. Therefore, the aim of our study was to analyze the distinctiveness of different psychological factors in predicting rehabilitation outcomes in a sample of patients with chronic low back pain (CLBP) in a rehabilitation setting. Research Method/Design: We conducted a longitudinal study using multivariable modeling taking into account a broad set of psychological variables as potential predictors. Rehabilitation outcome was assessed via health related quality of life (HRQL) and disease-specific functioning at the end of rehabilitation and six months later. The sample comprised N = 214 patients. Results: When considered separately, a range of psychological factors were significant predictors of HRQL and functioning at the end of rehabilitation and at six months follow-up, even if baseline values of outcome variables, sociodemographic variables, and baseline pain intensity are controlled. When considered in combination, a better work prognosis, self-efficacy and intensity of depressive symptoms were verified as independently significant predictors of HRQL. None of the psychological constructs remained significant predictors for disease-specific functioning. The incremental variance explained by the psychological constructs varied between 3 and 24%. Conclusions: The contribution of psychological factors may be different depending on the sample (acute vs. chronic) and the outcome domain. Future research should validate these results with respect to other patient-centered outcomes and in other CLBP samples.
Clinical features and outcomes of Merkel cell carcinoma in 20 cats.

The biological behaviour and prognostic factors of Merkel cell carcinoma (MCC) in 20 cats were studied. The tumours were surgically removed and histopathologically examined. The animals were 8 to 20 years old (median age: 14 years), and the tumours were predominantly located in the neck and head. Follow-up data were available in 17 cases, and 12 cats died within a year of surgery. The overall median survival time after resection was 243 days (range 16-360 days). Recurrence occurred in 11 cases, although 6 of them (55%) were found to be margin-negative. Possible metastasis occurred after the surgery in 10 cases, although 6 of them (60%) were found to be margin-negative. The histopathological features of MCC included tumour necrosis in 16 cases (80%), vascular invasion in 6 cases (38%) and high mitotic counts (median: 28.5 per high-power field). Irregular acanthosis was noted adjacent to the tumours in 9 cases (60%). Immunohistochemically, the tumour cells were positive for cytokeratin (CK) 20 and p63 in all cases, synaptophysin in 19 (95%) cases, and CK18 in 16 cases (80%). The study shows that feline MCC is associated with a poor prognosis and exhibited a strong tendency towards local recurrence, regional lymph node metastasis and distant spread.
Middle East Respiratory Syndrome Coronavirus Spike Protein Is Not Activated Directly by Cellular Furin during Viral Entry into Target Cells

Previous studies using the furin inhibitor dec-RVKR-CMK suggest that MERS-CoV utilizes a cellular protease, furin, to activate viral glycoproteins during cell entry. However, we found that dec-RVKR-CMK inhibits not only furin but also other proteases. Furthermore, we found no evidence that MERS-CoV uses furin. These findings suggest that previous studies in the virology field based on dec-RVKR-CMK should be reexamined carefully. Here we describe appropriate experiments that can be used to assess the effect of protease inhibitors on virus cell entry. ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes host cellular proteases to enter cells. A previous report shows that furin, which is distributed mainly in the Golgi apparatus and cycled to the cell surface and endosomes, proteolytically activates the MERS-CoV spike (S) protein following receptor binding to mediate fusion between the viral and cellular membranes. In this study, we reexamined furin usage by MERS-CoV using a real-time PCR-based virus cell entry assay after inhibition of cellular proteases. We found that the furin inhibitor dec-RVKR-CMK blocked entry of MERS-CoV harboring an S protein lacking furin cleavage sites; it even blocked entry into furin-deficient LoVo cells. In addition, dec-RVKR-CMK inhibited not only the enzymatic activity of furin but also those of cathepsin L, cathepsin B, trypsin, papain, and TMPRSS2. Furthermore, a virus cell entry assay and a cell-cell fusion assay provided no evidence that the S protein was activated by exogenous furin. Therefore, we conclude that furin does not play a role in entry of MERS-CoV into cells and that the inhibitory effect of dec-RVKR-CMK is specific for TMPRSS2 and cathepsin L rather than furin. IMPORTANCE Previous studies using the furin inhibitor dec-RVKR-CMK suggest that MERS-CoV utilizes a cellular protease, furin, to activate viral glycoproteins during cell entry. However, we found that dec-RVKR-CMK inhibits not only furin but also other proteases. Furthermore, we found no evidence that MERS-CoV uses furin. These findings suggest that previous studies in the virology field based on dec-RVKR-CMK should be reexamined carefully. Here we describe appropriate experiments that can be used to assess the effect of protease inhibitors on virus cell entry.
Barriers Block the Effect of Joint Attention on Working Memory: Perspective Taking Matters

Joint focus of attention between two individuals can influence the way that observers attend, encode, and value items. Using a nonpredictive gaze cuing task we previously found that working memory (WM) was better for jointly attended (validly cued) versus invalidly cued colored squares. Here we examine whether this influence of gaze on WM is driven by observers sharing the perspective of the face cue (mental state account), or simply by increased attention to the cued location (social attention account). To manipulate perspective taking, a closed barrier obstructed the cue face’s view of the memoranda, while an open barrier allowed the cue face to “see” the colors. A central cue face flanked by two identical barriers looked left or right, followed 500 ms later by colored squares for encoding which appeared equally often in the validly and invalidly cued locations. After a blank 1,000 ms maintenance interval, participants stated whether a probe color was present or not in the preceding display. When the barrier was open, WM was significantly impaired for invalidly versus validly cued items. When the barrier was closed, the effect of gaze cues on WM was abolished. In contrast, further experiments showed a significant cuing effect on the speed of simple target localization and color discrimination regardless of barrier type. These findings support the mental state account of joint attention in WM, whereby the attentional focus of another alters WM via higher level engagement with the second person perspective. A goal-specific model of perspective taking is proposed.
Retrotransposon-induced mosaicism in the neural genome

Over the past decade, major discoveries in retrotransposon biology have depicted the neural genome as a dynamic structure during life. In particular, the retrotransposon LINE-1 (L1) has been shown to be transcribed and mobilized in the brain. Retrotransposition in the developing brain, as well as during adult neurogenesis, provides a milieu in which neural diversity can arise. Dysregulation of retrotransposon activity may also contribute to neurological disease. Here, we review recent reports of retrotransposon activity in the brain, and discuss the temporal nature of retrotransposition and its regulation in neural cells in response to stimuli. We also put forward hypotheses regarding the significance of retrotransposons for brain development and neurological function, and consider the potential implications of this phenomenon for neuropsychiatric and neurodegenerative conditions.
Recent Progress in High‐Mobility Organic Transistors: A Reality Check

Over the past three decades, significant research efforts have focused on improving the charge carrier mobility of organic thin‐film transistors (OTFTs). In recent years, a commonly observed nonlinearity in OTFT current–voltage characteristics, known as the “kink” or “double slope,” has led to widespread mobility overestimations, contaminating the relevant literature. Here, published data from the past 30 years is reviewed to uncover the extent of the field‐effect mobility hype and identify the progress that has actually been achieved in the field of OTFTs. Present carrier‐mobility‐related challenges are identified, finding that reliable hole and electron mobility values of 20 and 10 cm2 V−1 s−1, respectively, have yet to be achieved. Based on the analysis, the literature is then reviewed to summarize the concepts behind the success of high‐performance p‐type polymers, along with the latest understanding of the design criteria that will enable further mobility enhancement in n‐type polymers and small molecules, and the reasons why high carrier mobility values have been consistently produced from small molecule/polymer blend semiconductors. Overall, this review brings together important information that aids reliable OTFT data analysis, while providing guidelines for the development of next‐generation organic semiconductors.
Systematic review and network meta-analysis of clinical outcomes associated with isavuconazole versus relevant comparators for patients with invasive aspergillosis

Abstract Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA. Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model. Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3–5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (−1.39 [−2.21, −0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [−1.17, 1.53], 0.50 [−1.11, 2.13] and 0.32 [−0.19, 0.84], respectively) or overall response (−0.99 [−2.21, 0.29], −0.89 [−2.41, 0.65] and 0.06 [−0.43, 0.57], respectively). Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.
Iron-dependent cleavage of ribosomal RNA during oxidative stress in the yeast Saccharomyces cerevisiae

Stress-induced strand breaks in rRNA have been observed in many organisms, but the mechanisms by which they originate are not well-understood. Here we show that a chemical rather than an enzymatic mechanism initiates rRNA cleavages during oxidative stress in yeast (Saccharomyces cerevisiae). We used cells lacking the mitochondrial glutaredoxin Grx5 to demonstrate that oxidant-induced cleavage formation in 25S rRNA correlates with intracellular iron levels. Sequestering free iron by chemical or genetic means decreased the extent of rRNA degradation and relieved the hypersensitivity of grx5Δ cells to the oxidants. Importantly, subjecting purified ribosomes to an in vitro iron/ascorbate reaction precisely recapitulated the 25S rRNA cleavage pattern observed in cells, indicating that redox activity of the ribosome-bound iron is responsible for the strand breaks in the rRNA. In summary, our findings provide evidence that oxidative stress–associated rRNA cleavages can occur through rRNA strand scission by redox-active, ribosome-bound iron that potentially promotes Fenton reaction–induced hydroxyl radical production, implicating intracellular iron as a key determinant of the effects of oxidative stress on ribosomes. We propose that iron binding to specific ribosome elements primes rRNA for cleavages that may play a role in redox-sensitive tuning of the ribosome function in stressed cells.
Bayesian Argumentation and the Value of Logical Validity

According to the Bayesian paradigm in the psychology of reasoning, the norms by which everyday human cognition is best evaluated are probabilistic rather than logical in character. Recently, the Bayesian paradigm has been applied to the domain of argumentation, in which the fundamental norms are traditionally assumed to be logical. Here, we present a major generalization of extant Bayesian approaches to argumentation that (a) utilizes a new class of Bayesian learning methods that are better suited to modeling dynamic and conditional inferences than standard Bayesian conditionalization, (b) is able to characterize the special value of logically valid argument schemes in uncertain reasoning contexts, (c) greatly extends the range of inferences and argumentative phenomena that can be adequately described in a Bayesian framework, and (d) undermines some influential theoretical motivations for dual function models of human cognition. We conclude that the probabilistic norms given by the Bayesian approach to rationality are not necessarily at odds with the norms given by classical logic. Rather, the Bayesian theory of argumentation can be seen as justifying and enriching the argumentative norms of classical logic.
Bi-directional longitudinal associations between different types of bullying victimization, suicide ideation/attempts, and depression among a large sample of European adolescents.

BACKGROUND The association between bullying victimization and depression, suicide ideation and suicide attempts has been studied mainly in cross-sectional studies. This study aims to test the bidirectional effect and the chronicity versus sporadic effect of physical, verbal, and relational bullying victimization on suicidal ideation/attempts and depression. METHODS Longitudinal assessments with an interval of 3- and 12-months were performed within a sample of 2,933 adolescents (56.1% females; mean age 14.78, SD = .89) from 10 European countries, participating in the Saving and Empowering Young Lives in Europe (SEYLE) school-based multicenter control sample. Multilevel Structural Equation Models were used, controlling for sociodemographic variables. Victimization was considered chronic when a student was victimized in the first two time points and sporadic when it was reported only at one point but not in another. RESULTS Bidirectional prospective association between all types of victimization and depression were found. Among participants, who reported victimization once (but not twice), physical victimization, but not verbal and relational, was associated with later suicidal ideation and attempts. Chronic victimization of any type increased likelihood for later depression compared with sporadic and no-victimization. Chronic relational victimization increased the likelihood of later suicidal ideation, and chronic physical victimization increased the likelihood for suicidal attempts. CONCLUSIONS The results support the bidirectional effect of victimization and depression and indicate that there are complex longitudinal associations between victimization and suicidal ideation/attempts. Physical victimization may especially carry effect on suicidal risk over time. Interventions should focus on victimization as a cause of distress but also aim to prevent vulnerable adolescents from becoming targets of victimization.
ACOs with risk-bearing experience are likely taking steps to reduce low-value medical services.

OBJECTIVES Accountable care organizations (ACOs) are groups of healthcare providers responsible for quality of care and spending for a defined patient population. The elimination of low-value medical services will improve quality and reduce costs and, therefore, ACOs should actively work to reduce the use of low-value services. We set out to identify ACO characteristics associated with implementation of strategies to reduce overuse. STUDY DESIGN Survey analysis. METHODS We used the National Survey of ACOs to determine the percentage of responding ACOs aware of the Choosing Wisely campaign and to what degree ACOs have taken steps to reduce the use of low-value services. We identified characteristics of ACOs associated with implementing low-value care-reducing strategies using 3 statistical models (stepwise and LASSO logistic regression and random forest). RESULTS Responding executives of 155 of 267 ACOs (58%) were aware of Choosing Wisely. Eighty-four of those 155 ACO leaders said that their ACOs also actively implemented strategies to reduce the use of low-value services, largely through educating physicians and stimulating shared decision making. All 3 models identified the presence of at least 1 commercial payer contract and prior joint experience pursuing risk-based payment contracts as the most important predictors of an ACO actively implementing strategies to reduce low-value care. CONCLUSIONS In the first year of implementation, just one-third of ACOs had taken steps to reduce the use of low-value medical services. Safety-net ACOs and those with little experience as a risk-bearing organization need more time and support from healthcare payers and the Choosing Wisely campaign to prioritize the reduction of overuse.
Photosensitivity and type I IFN responses in cutaneous lupus are driven by epidermal-derived interferon kappa

Objective Skin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin. Methods mRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin. Results IFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10−04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis. Conclusion Collectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.
Altered editing level of microRNAs is a potential biomarker in lung adenocarcinoma

Adenosine‐to‐inosine (A‐to‐I) microRNA editing is associated with tumor phenotypes in various cancer types. Recent analyses of The Cancer Genome Atlas (TCGA) dataset have shown several microRNAs that undergo A‐to‐I editing in human cancers, some of which have been reported to be associated with prognosis. Herein, we examined published small RNA deep sequencing data of 74 cases of lung adenocarcinoma (AD) and the corresponding normal counterpart (NC) specimen in silico in order to identify A‐to‐I microRNA editing events. Editing levels of miR‐379‐5p, miR‐99a‐5p, and miR‐497‐5p were lower in AD than in NC and, in a large number of cases, the editing level of miR‐200b‐3p was higher in AD than in NC. Difference in the editing level between AD and NC was largest for miR‐99a‐5p. Then, we examined the editing level of miR‐99a‐5p in 50 surgically resected lung adenocarcinoma cases at our institution by a conventional sequence‐based method, and its association with clinical outcomes. The editing level of miR‐99a‐5p was significantly lower in 19 cases of AD (38%) than in corresponding NC. These cases showed a shorter overall survival as assessed using the log‐rank test (P = .047). This trend was consistent with previous analyses of TCGA dataset. The altered editing level of microRNAs in lung adenocarcinoma could serve as a potential biomarker.