Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic Alterations as Potential Therapeutic Targets in Extramammary Paget's Disease of the Vulva.

PURPOSE To identify genomic alterations as potential therapeutic targets in extramammary Paget disease (EMPD) of the vulva. METHODS We identified all patients with primary vulvar EMPD who were treated at our institution and underwent paired tumor-normal massively parallel sequencing of 410-468 cancer-related genes (MSK-IMPACT assay). EMPD of the vulva samples sequenced from 2014 to 2019 were reviewed and somatic mutations identified, with specific focus on mutations of potential therapeutic targets. Clinical data were abstracted from electronic medical records. Microsatellite instability (MSI) was assessed by MSIscore. RESULTS Tumors of 26 patients with EMPD underwent genomic sequencing. At diagnosis, all patients had noninvasive or microinvasive (< 1 mm) disease; invasive disease eventually developed in 2 patients. Primary treatment was surgery for 19 patients (73%) and imiquimod topical therapy for 7 (27%). Seven patients had ≥ 2 surgeries as part of clinical course (1 patient had 5 vulvar resections). Samples had a median of 2 coding mutations in the genes analyzed (range, 0-29). The most common mutations were in PIK3CA (n = 9; 35%), ERBB2 (4 mutations and 3 copy number alterations; 27%), and TP53 (n = 7; 27%). MSIscore was available for 23 samples; all were microsatellite stable. After tumor genomic profiling, a patient who was initially treated with multiple resections and imiquimod was found to have a PIK3CA p.E542K mutation. She underwent PI3K-inhibitor treatment for 18 months before disease progression. CONCLUSION EMPD of the vulva has a chronic and relapsing course, often requiring multiple surgical resections. Effective topical treatments are lacking. We identified targetable mutations (PIK3CA or ERBB2) in > 25% of a real-world clinical cohort. Additional prospective research implementing targetable therapies for EMPD treatment is warranted.
Penguins, Birds, and Pilot Knowledge: Can an Overlooked Attribute of Human Cognition Explain Our Most Puzzling Aircraft Accidents?

Objective We extend the theory of conceptual categories to flight safety events, to understand variations in pilot event knowledge. Background Experienced, highly trained pilots sometimes fail to recognize events, resulting in procedures not being followed, damaging safety. Recognition is supported by typical, representative members of a concept. Variations in typicality (“gradients”) could explain variations in pilot knowledge, and hence recognition. The role of simulations and everyday flight operations in the acquisition of useful, flexible concepts is poorly understood. We illustrate uses of the theory in understanding the industry-wide problem of nontypical events. Method One hundred and eighteen airline pilots responded to scenario descriptions, rating them for typicality and indicating the source of their knowledge about each scenario. Results Significant variations in typicality in flight safety event concepts were found, along with key gradients that may influence pilot behavior. Some concepts were linked to knowledge gained in simulator encounters, while others were linked to real flight experience. Conclusion Explicit training of safety event concepts may be an important adjunct to what pilots may variably glean from simulator or operational flying experiences, and may result in more flexible recognition and improved response. Application Regulators, manufacturers, and training providers can apply these principles to develop new approaches to pilot training that better prepare pilots for event diversity.
Dietary saturated fats and apolipoprotein B48 levels are similarly associated with cognitive decline in healthy older aged Australians.

BACKGROUND AND OBJECTIVES As the incidence and prevalence of Alzheimer's disease increases, so does the body of epidemiological and clinical research that suggests a relationship between dietary fatty acids, in particular saturates, and cognitive decline. In this study, we investigated the association between serum apolipoprotein B48 (apoB48), saturated fatty acid intake and consumption behaviour, and cognitive performance, in healthy, older aged Australians. METHODS AND STUDY DESIGN We retrospectively analysed fasted serum apoB48 concentrations, food frequency questionnaire, and cognitive performance data collected from 147 participants (98F|49M) over the age of 50. We used Spearman's correlations and a nested domain model to evaluate the relationship between serum apoB48, dietary behaviour and measures of cognitive performance. RESULTS Overall, we found that higher fasted apoB48 concentrations, and/or dietary behaviours which led to increased dietary consumption of diets high in saturated fatty acids, were inversely associated with cognition. Interestingly however, dietary behaviour patterns of saturated fatty acid consumption and serum apoB48 were linked with better secondary memory and perceptual speed, respectively. CONCLUSIONS This is the first time that fasted apoB48 has been implicated as a biomarker for cognitive decline and Alzheimer's disease risk.
A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow‐Fed Young Adult Mice

Oxidized phospholipids containing phosphocholine (OxPL) are pro‐inflammatory lipid peroxidation products that bind to scavenger receptors (SRs), such as Scarb1, and toll‐like receptors (TLRs). Excessive OxPL, as found in oxidized low‐density lipoprotein (OxLDL), overwhelm these defense mechanisms and become pathogenic in atherosclerosis, nonalcoholic steatohepatitis (NASH), and osteoporosis. We previously reported that the innate IgM natural antibody E06 binds to OxPL and neutralizes their deleterious effects; expression of the single‐chain (scFv) form of the antigen‐binding domain of E06 (E06‐scFv) as a transgene increases trabecular bone in male mice. We show herein that E06‐scFv increases trabecular and cortical bone in female and male mice by increasing bone formation and decreasing osteoblast apoptosis in vivo. Homozygous E06‐scFv mice have higher bone mass than hemizygous, showing a dose effect of the transgene. To investigate how OxPL restrain bone formation under physiologic conditions, we measured the levels of SRs and TLRs that bind OxPL. We found that osteoblastic cells primarily express Scarb1. Moreover, OxLDL‐induced apoptosis and reduced differentiation were prevented in bone marrow–derived or calvaria‐derived osteoblasts from Scarb1 knockout mice. Because Scarb1‐deficient mice are reported to have high bone mass, our results suggest that E06 may promote bone anabolism in healthy young mice, at least in part, by neutralizing OxPL, which in turn promote Scarb1‐mediated apoptosis of osteoblasts or osteoblast precursors. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Ultra Trail Performance is Differently Predicted by Endurance Variables in Men and Women

Abstract The study aimed to assess the relationship between peak oxygen uptake, ventilatory thresholds and maximal fat oxidation with ultra trail male and female performance. 47 athletes (29 men and 18 women) completed a cardiopulmonary exercise test between 2 to 4 weeks before a 107-km ultra trail. Body composition was also analyzed using a bioelectrical impedance weight scale. Exploratory correlation analyses showed that peak oxygen uptake (men: r=–0.63, p=0.004; women: r=–0.85, p < 0.001), peak speed (men: r=–0.74, p < 0.001; women: r=–0.69, p=0.009), speed at first (men: r=–0.49, p=0.035; women: r=–0.76, p=0.003) and second (men: r=–0.73, p < 0.001; women: r=–0.76, p=0.003) ventilatory threshold, and maximal fat oxidation (men: r=–0.53, p=0.019; women: r=–0.59, p=0.033) were linked to race time in male and female athletes. Percentage of fat mass (men: r=0.58, p=0.010; women: r=0.62, p= 0.024) and lean body mass (men: r=–0.61, p=0.006; women: r=–0.61, p=0.026) were also associated with performance in both sexes. Subsequent multiple regression analyses revealed that peak speed and maximal fat oxidation together were able to predict 66% of male performance; while peak oxygen uptake was the only statistically significant variable explaining 69% of the variation in women’s race time. These results, although exploratory in nature, suggest that ultra trail performance is differently predicted by endurance variables in men and women.
Association between overweight/obesity with depression, anxiety, low self-esteem, and body dissatisfaction in children and adolescents: a systematic review and meta-analysis of observational studies

Abstract Purpose Childhood and Adolescent overweight and obesity may be associated with psychological problems. We aimed to conduct a systematic review and summarize published articles on the association between overweight/obesity with risk of depression, anxiety, low self-esteem, and body dissatisfaction among children and adolescents. Methods PubMed and Scopus databases were used to conduct a comprehensive search and identify eligible literature published prior to July 2020. The random-effects models (DerSimonian–Laird method) were applied to pool the effect sizes. Subgroup analysis was performed to find potential sources of heterogeneity. Results 28 studies (3 prospective cohorts and 25 cross-sectional) were included in the current systematic review and meta-analysis. The total sample sizes ranged from 244 to 60252. A positive significant association was found between overweight (pooled risk estimate: 1.15, 95% CI: 1.00–1.31, P = 0.04) and obesity (pooled risk estimate: 1.53, 95% CI: 1.16–2.02, P = 0.003) with risk of low self-esteem, respectively. A significant positive association was found between obesity and risk of body dissatisfaction (pooled risk estimate: 4.05, 95% CI: 2.34–7.023, P = 0.0001). Moreover, no association was found between overweight and risk of body dissatisfaction among children and adolescents. Also, no association was observed between overweight/obesity and risk of depression and anxiety. Conclusions Findings showed a positive association between obesity and the risk of body dissatisfaction and low self-esteem among children and adolescents. Moreover, there was a significant positive association between overweight and the risk of low self-esteem.
Thermal requirement of oilseed Brassica cultivars at different phenological stages under varying environmental conditions

Field experiments were conducted during three post rainy (rabi) seasons of 2001-2004 at Bharatpur, New Delhi and Mohanpur to study the effect of sowing dates and cultural environment on accumulation of growing degree-days vis-a-vis occurrence of different phenological events on oilseed Brassica cultivars 'Varuna', 'Rohini', 'Pusa Jaikisan' [Brassica juncea (L.) Czem. and Coss. ] and 'Binoy' (B, rapa L. var yellow sarson) sown at seven-day intervals starting from 1 October. October sown crop recorded higher seed yield due to exposure to higher growing degree-days. Variations were also noticed among locations. Equation developed from the study can be used for simulation of phenology and growth of mustard.
Feed digestibility in different intestinal parts of chickens.

単冠白色レグホーン種成雄を用いて空腸遠位端,回腸中央部,回腸遠位端および直腸遠位端の4部位にそれぞれフィステルを装着し,各部位より排泄物を採取して飼料の消化率と消化管内通過時間を測定した. 供試飼料は配合飼料のほか,とうもろこし,小麦,玄米,大麦,マイロ,裸麦の各単味飼料と,玄米-大豆,玄米-魚粉の各混合飼料とし,これら飼料中に混入した酸化クロム(0.5%)を指標物質として各成分の消化率を算出した. 飼料摂取量は,飼料間では差が大きかったがフィステル装着部位による影響は比較的小さい傾向がみられた. 飼料の消化率は,各成分とも飼料の種類により各部位間でかなりの差が示された. しかし全飼料の平均でみると,粗蛋白質は各部位間において,粗脂肪と可溶無窒素物は回腸中央部以降において消化率にほとんど差が示されなかった. 粗繊維の消化率は空腸遠位端でとくに低い値がみられたが,バラツキが大きいために有意な差ではなかった. 飼料の消化管通過時間は,全過程(直腸遠位端)を通過する時間のみならず,各部位の通過パターンにも飼料間で差異のあることが明らかになった. 以上の結果は,鶏ではとくに近位の腸管で飼料成分は大部分が消化吸収されている可能性を示唆している.
Multi-Omic Analysis Reveals Different Effects of Sulforaphane on the Microbiome and Metabolome in Old Compared to Young Mice

Dietary factors modulate interactions between the microbiome, metabolome, and immune system. Sulforaphane (SFN) exerts effects on aging, cancer prevention and reducing insulin resistance. This study investigated effects of SFN on the gut microbiome and metabolome in old mouse model compared with young mice. Young (6–8 weeks) and old (21–22 months) male C57BL/6J mice were provided regular rodent chow ± SFN for 2 months. We collected fecal samples before and after SFN administration and profiled the microbiome and metabolome. Multi-omics datasets were analyzed individually and integrated to investigate the relationship between SFN diet, the gut microbiome, and metabolome. The SFN diet restored the gut microbiome in old mice to mimic that in young mice, enriching bacteria known to be associated with an improved intestinal barrier function and the production of anti-inflammatory compounds. The tricarboxylic acid cycle decreased and amino acid metabolism-related pathways increased. Integration of multi-omic datasets revealed SFN diet-induced metabolite biomarkers in old mice associated principally with the genera, Oscillospira, Ruminococcus, and Allobaculum. Collectively, our results support a hypothesis that SFN diet exerts anti-aging effects in part by influencing the gut microbiome and metabolome. Modulating the gut microbiome by SFN may have the potential to promote healthier aging.
Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.
Mast Cells in the Auditory Periphery of Rodents

Mast cells (MCs) are densely granulated cells of myeloid origin and are a part of immune and neuroimmune systems. MCs have been detected in the endolymphatic sac of the inner ear and are suggested to regulate allergic hydrops. However, their existence in the cochlea has never been documented. In this work, we show that MCs are present in the cochleae of C57BL/6 mice and Wistar rats, where they localize in the modiolus, spiral ligament, and stria vascularis. The identity of MCs was confirmed in cochlear cryosections and flat preparations using avidin and antibodies against c-Kit/CD117, chymase, tryptase, and FcεRIα. The number of MCs decreased significantly during postnatal development, resulting in only a few MCs present in the flat preparation of the cochlea of a rat. In addition, exposure to 40 µM cisplatin for 24 h led to a significant reduction in cochlear MCs. The presence of MCs in the cochlea may shed new light on postnatal maturation of the auditory periphery and possible involvement in the ototoxicity of cisplatin. Presented data extend the current knowledge about the physiology and pathology of the auditory periphery. Future functional studies should expand and translate this new basic knowledge to clinics.
Introducing a comprehensive high-stake online exam to final-year dental students during the COVID-19 pandemic and evaluation of its effectiveness

ABSTRACT Background Dental education involves teaching and assessing the acquisition of verifiable domains that require superior psychomotor, communication, and cognitive skills. Evolving technologies and methods of assessment could enhance student learning environment and improve tutor assessment experience. Objective The aim of this study was to introduce the application of a comprehensive high-stakes online exam to final-year dental students during the COVID-19 pandemic and evaluate its effectiveness. Design A high-stakes exam was introduced and implemented online to the final-year dental students prior to their graduation. The exam consisted of four components: MEQs, MCQs, OSCE and an oral exam. The exam and invigilation were conducted using Blackboard and MS Teams programs. Stakeholders’ views of the exam were obtained using two tailored surveys, one for students and another for faculty; both included closed- and open-ended questions. Results The exam was run successfully without untoward events. Both students and staff were satisfied with the online exam with the latter being more satisfied than the former. Students with previous experience in online learning system were more satisfied with the online exam compared with those with less experience (p < 0.05). The main issues raised by students’ satisfaction with the exam were: inadequacy of time for the MEQ part, prevention of back tracking in the MCQ part and minor technological issues, whereas those raised by faculty members were increased time required to complete the exam setup and grading compared to the paper-based exam and minor technological issues. Conclusions A newly introduced, multi-format, online high-stakes exam was implemented successfully to final-year dental students with minor technological issues and good satisfaction by students and staff alike.
Retrograde signaling from the mitochondria to the nucleus translates the positive effect of ethylene on dormancy breaking of Arabidopsis thaliana seeds.

Ethylene and Reactive Oxygen Species (ROS) regulate seed dormancy alleviation, but the molecular basis of their action and crosstalk remains largely unknown. Here we studied the mechanism of Arabidopsis seed dormancy release by ethylene using cell imaging, genetic and transcriptomics approaches, in order to tackle its possible interaction with ROS homeostasis. We found that the effect of ethylene on seed germination required ROS production by the mitochondrial electron transport chain. Seed response to ethylene involved mitochondrial retrograde response (MRR) through nuclear ROS production and up-regulation of the MRR components AOX1a and ANAC013, but it also required the activation of the ethylene canonical pathway. Together our data allow deciphering the mode of action of ethylene on seed germination and the associated dynamics of ROS production. Our findings highlight the occurrence of retrograde signaling in seed germination.
Venous thromboembolism after ultrasound guided foam sclerotherapy

Objective To analyze prevalence of venous thromboembolism (VTE) after ultrasound guided foam sclerotherapy. Method Clinical retrospective study with patients treated from 2004 to 2014. Charts with incomplete data and follow-up less than 60 days were excluded. Polidocanol foam (Tessari method) was used. The primary outcome was the prevalence of VTE and the secondary were possible risk factors. Chi-square test and Marascuillo prodecure were applied at a significance level of 5%. Results 2,616 patients were included with 4,712 lower limbs treated. The mean age was 50.7±0.86, in majority female, 83.7%. VTE occurred in 0.49% (pulmonary embolism 0,3%) in a mean time of 44.0±42.2 days. Male gender, personal or family history of phlebitis or DVT and high caliber varicose veins were significantly associated to VTE. Conclusion incidence of VTE is low, male gender, personal or family history of VTE and caliber of varicose veins greater than 7 mm increased the risk.
Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study

Voriconazole is a broad‐spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction.
Rapid detection of tuberculosis in remote Alaska

ABSTRACT In a remote region of western Alaska where tuberculosis (TB) incidence remains relatively high, a rapid molecular detection assay (Xpert MTB/RIF) was introduced four years ago with goal of improving the ability to diagnose active pulmonary tuberculosis (TB). Our aggressive testing programme was intended for all patients acutely evaluated for pulmonary TB at our regional hospital and multiple clinics over a large area. All 223 consecutive patients evaluated for active pulmonary TB were tested with Xpert MTB/RIF (Xpert) per our protocol of which 192 (86.1%) had at least one additional (paired) sputum sample collected for standard acid-fast bacilli (smear) microscopy and culture. Fourteen patients eventually became culture-positive for Mycobacterium tuberculosis (MTB), all but one having initially tested positive (MTB detected) by Xpert (sensitivity 92.9%). All remaining culture-negative individuals had tested negative (not detected) by Xpert (specificity 100%). By contrast, smear microscopy sensitivity and specificity was 64.3% and 98.9% respectively. This represents the addition of four active TB patients detected by Xpert over smear. In remote regions, the ability of Xpert to quickly and reliably detect TB while determine which patients are not contagious represents a huge healthcare savings as in most cases these patients will not require hospitalized isolation.
Testing the Effects of COVID-19 Confinement in Spanish Children: The Role of Parents’ Distress, Emotional Problems and Specific Parenting

The present study aimed to examine the effects of the Spanish confinement derived from the COVID-19 crisis on children and their families, accounting for child’s age. A range of child negative (e.g., conduct problems) and positive outcomes (e.g., routine maintenance) were examined, along with a set of parent-related variables, including resilience, perceived distress, emotional problems, parenting distress and specific parenting practices (e.g., structured or avoidant parenting), which were modeled through path analysis to better understand child adjustment. Data were collected in April 2020, with information for the present study provided by 940 (89.6%) mothers, 102 (9.7%) fathers and 7 (0.7%) different caregivers, who informed on 1049 Spanish children (50.4% girls) aged 3 to 12 years (Mage = 7.29; SD = 2.39). The results suggested that, according to parents’ information, most children did not show important changes in behavior, although some increasing rates were observed for both negative and positive outcomes. Child adjustment was influenced by a chain of effects, derived from parents’ perceived distress and emotional response to the COVID-19 crisis, via parenting distress and specific parenting practices. While parenting distress in particular triggered child negative outcomes, specific parenting practices were more closely related to child positive outcomes. These findings may help to better inform, for potential future outbreaks, effective guidelines and prevention programs aimed at promoting the child’s well-being in the family.