Miracle-dz/UniFAR-FTUs huggingface dataset:
Effective Perturbations of the Amplitude, Gating, and Hysteresis of IK(DR) Caused by PT-2385, an HIF-2α Inhibitor

PT-2385 is currently regarded as a potent and selective inhibitor of hypoxia-inducible factor-2α (HIF-2α), with potential antineoplastic activity. However, the membrane ion channels changed by this compound are obscure, although it is reasonable to assume that the compound might act on surface membrane before entering the cell´s interior. In this study, we intended to explore whether it and related compounds make any adjustments to the plasmalemmal ionic currents of pituitary tumor (GH3) cells and human 13-06-MG glioma cells. Cell exposure to PT-2385 suppressed the peak or late amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner, with IC50 values of 8.1 or 2.2 µM, respectively, while the KD value in PT-2385-induced shortening in the slow component of IK(DR) inactivation was estimated to be 2.9 µM. The PT-2385-mediated block of IK(DR) in GH3 cells was little-affected by the further application of diazoxide, cilostazol, or sorafenib. Increasing PT-2385 concentrations shifted the steady-state inactivation curve of IK(DR) towards a more hyperpolarized potential, with no change in the gating charge of the current, and also prolonged the time-dependent recovery of the IK(DR) block. The hysteretic strength of IK(DR) elicited by upright or inverted isosceles-triangular ramp voltage was decreased during exposure to PT-2385; meanwhile, the activation energy involved in the gating of IK(DR) elicitation was noticeably raised in its presence. Alternatively, the presence of PT-2385 in human 13-06-MG glioma cells effectively decreased the amplitude of IK(DR). Considering all of the experimental results together, the effects of PT-2385 on ionic currents demonstrated herein could be non-canonical and tend to be upstream of the inhibition of HIF-2α. This action therefore probably contributes to down-streaming mechanisms through the changes that it or other structurally resemblant compounds lead to in the perturbations of the functional activities of pituitary cells or neoplastic astrocytes, in the case that in vivo observations occur.
Trust, power and learning in workplace‐based assessment: The trainee perspective

For trainees to participate meaningfully in workplace‐based assessment (WBA), they must have trust in their assessor. However, the trainee's dependent position complicates such trust. Understanding how power and trust influence WBAs may help us make them more effective learning opportunities. We conducted semi‐structured interviews with 17 postgraduate anaesthesia trainees across Australia and New Zealand. Sensitised by notions of power, we used constructivist grounded theory methodology to examine trainees' experiences with trusting their supervisors in WBAs. In our trainee accounts, we found that supervisors held significant power to mediate access to learning opportunities and influence trainee progress in training. All episodes where supervisors could observe trainees, from simply working together to formal WBAs, were seen to generate assessment information with potential consequences. In response, trainees actively acquiesced to a deferential role, which helped them access desirable expertise and minimise the risk of reputational harm. Trainees granted trust based on how they anticipated a supervisor would use the power inherent in their role. Trainees learned to ration exposure of their authentic practice to supervisors in proportion to their trust in them. Trainees were more trusting and open to learning when supervisors used their power for the trainee's benefit and avoided WBAs with supervisors they perceived as less trustworthy. If assessment for learning is to flourish, then the trainee–supervisor power dynamic must evolve. Enhancing supervisor behaviour through reflection and professional development to better reward trainee trust would invite more trainee participation in assessment for learning. Modifying the assessment system design to nudge the power balance towards the trainee may also help. Modifications could include designated formative and summative assessments or empowering trainees to select which assessments count towards progress decisions. Attending to power and trust in WBA may stimulate progress towards the previously aspirational goal of assessment for learning in the workplace.
Can uric acid blood levels in renal transplant recipients predict allograft outcome?

Abstract Background Hyperuricemia is common after renal transplantation, especially in those receiving calcineurin inhibitors. Little, however, is known about the relationship between uric acid (UA) levels and allograft outcome. Methods We conducted a retrospective single-center analysis (N = 368) in order to assess UA blood levels post-transplant association with allograft outcome. For this study, a median serum UA level of all measured UA levels from 1 month to 1 year post renal transplantation was calculated. Results Patients were divided into 2 groups based on the median UA level measured between 1 and 12 months post-transplant. Those with median UA level ≥ 7 and ≥ 6 mg/dL (N = 164) versus median UA level < 7 and < 6 mg/dL for men and women respectively (N = 204) had lower GFR values at 1, 3 and 5 years posttransplant (mean GFR ± SD of 43.4 ± 20.6 and 58 ± 19.9 at 3 years post-transplant, p < 0.001). In multivariate models, UA levels were no longer significantly associated with renal allograft function. In a multivariate cox proportional hazard model, UA level was found to be independently associated with increased risk for death-censored graft loss (HR of 1.3, 95% CI 1.0–1.7, p < 0.05 for every increase of 1 mg/dL in UA level). Conclusion Hyperuricemia was found to be associated with increased death- censored graft loss but not with allograft function. Increased UA levels were not found to be an independent predictor of long-term allograft function despite the known association of hyperuricemia with the progression of cardiovascular and renal disease.
HiLo Based Line Scanning Temporal Focusing Microscopy for High-Speed, Deep Tissue Imaging

High-speed, optical-sectioning imaging is highly desired in biomedical studies, as most bio-structures and bio-dynamics are in three-dimensions. Compared to point-scanning techniques, line scanning temporal focusing microscopy (LSTFM) is a promising method that can achieve high temporal resolution while maintaining a deep penetration depth. However, the contrast and axial confinement would still be deteriorated in scattering tissue imaging. Here, we propose a HiLo-based LSTFM, utilizing structured illumination to inhibit the fluorescence background and, thus, enhance the image contrast and axial confinement in deep imaging. We demonstrate the superiority of our method by performing volumetric imaging of neurons and dynamical imaging of microglia in mouse brains in vivo.
The expression of PHB2 in the cochlea: Possible relation to age‐related hearing loss

Age‐related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly, but its mechanism remains unclear. Scaffold protein prohibitin 2 (PHB2) has been widely involved in aging and neurodegeneration. However, the role of PHB2 in ARHL is undeciphered to date. To investigate the expression pattern and the role of PHB2 in ARHL, we used C57BL/6 mice and HEI‐OC1 cell line as models. In our study, we have found PHB2 exists in the cochlea and is expressed in hair cells, spiral ganglion neurons, and HEI‐OC1 cells. In mice with ARHL, mitophagy is reduced and correspondingly the expression level of PHB2 is decreased. Moreover, after H2O2 treatment the mitophagy is activated and the PHB2 expression is increased. These findings indicate that PHB2 may exert an important role in ARHL through mitophagy. Findings from this study will be helpful for elucidating the mechanism underlying the ARHL and for providing a new target for ARHL treatment.
Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology

The severity of lesions that develop in patients infected by Leishmania braziliensis is mainly associated with a highly cytotoxic and inflammatory cutaneous environment. Recently, we demonstrated that senescent T and NK cells play a role in the establishment and maintenance of this tissue inflammation. Here, we extended those findings using transcriptomic analyses that demonstrate a strong co‐induction of senescence and pro‐inflammatory gene signatures in cutaneous leishmaniasis (CL) lesions. The senescence‐associated signature was characterized by marked expression of key genes such as ATM, Sestrin 2, p16, p21 and p38. The cell type identification from deconvolution of bulk sequencing data showed that the senescence signature was linked with CD8+ effector memory and TEMRA subsets and also senescent NK cells. A key observation was that the senescence markers in the skin lesions are age‐independent of patients and were correlated with lesion size. Moreover, a striking expression of the senescence‐associated secretory phenotype (SASP), pro‐inflammatory cytokine and chemokines genes was found within lesions that were most strongly associated with the senescent CD8 TEMRA subset. Collectively, our results confirm that there is a senescence transcriptomic signature in CL lesions and supports the hypothesis that lesional senescent cells have a major role in mediating immunopathology of the disease.
Structural Arrangement Produced by Concanavalin A Binding to Homomeric GluK2 Receptors

Kainate receptors are members of the ionotropic glutamate receptor family. They form cation-specific transmembrane channels upon binding glutamate that desensitize in the continued presence of agonists. Concanavalin A (Con-A), a lectin, stabilizes the active open-channel state of the kainate receptor and reduces the extent of desensitization. In this study, we used single-molecule fluorescence resonance energy transfer (smFRET) to investigate the conformational changes underlying kainate receptor modulation by Con-A. These studies showed that Con-A binding to GluK2 homomeric kainate receptors resulted in closer proximity of the subunits at the dimer–dimer interface at the amino-terminal domain as well as between the subunits at the dimer interface at the agonist-binding domain. Additionally, the modulation of receptor functions by monovalent ions, which bind to the dimer interface at the agonist-binding domain, was not observed in the presence of Con-A. Based on these results, we conclude that Con-A modulation of kainate receptor function is mediated by a shift in the conformation of the kainate receptor toward a tightly packed extracellular domain.
The value of primary transcripts to the clinical and non‐clinical genomics community: Survey results and roadmap for improvements

Variant interpretation is dependent on transcript annotation and remains time consuming and challenging. There are major obstacles for historical data reuse and for interpretation of new variants. First, both RefSeq and Ensembl/GENCODE produce transcript sets in common use, but there is currently no easy way to translate between the two. Second, the resources often used for variant interpretation (e.g. ClinVar, gnomAD, UniProt) do not use the same transcript set, nor default transcript or protein sequence.
Factors influencing the effectiveness of remote patient monitoring interventions: a realist review

Objectives Our recent systematic review determined that remote patient monitoring (RPM) interventions can reduce acute care use. However, effectiveness varied within and between populations. Clinicians, researchers, and policymakers require more than evidence of effect; they need guidance on how best to design and implement RPM interventions. Therefore, this study aimed to explore these results further to (1) identify factors of RPM interventions that relate to increased and decreased acute care use and (2) develop recommendations for future RPM interventions. Design Realist review—a qualitative systematic review method which aims to identify and explain why intervention results vary in different situations. We analysed secondarily 91 studies included in our previous systematic review that reported on RPM interventions and the impact on acute care use. Online databases PubMed, EMBASE and CINAHL were searched in October 2020. Included studies were published in English during 2015–2020 and used RPM to monitor an individual’s biometric data (eg, heart rate, blood pressure) from a distance. Primary and secondary outcome measures Contextual factors and potential mechanisms that led to variation in acute care use (hospitalisations, length of stay or emergency department presentations). Results Across a range of RPM interventions 31 factors emerged that impact the effectiveness of RPM innovations on acute care use. These were synthesised into six theories of intervention success: (1) targeting populations at high risk; (2) accurately detecting a decline in health; (3) providing responsive and timely care; (4) personalising care; (5) enhancing self-management, and (6) ensuring collaborative and coordinated care. Conclusion While RPM interventions are complex, if they are designed with patients, providers and the implementation setting in mind and incorporate the key variables identified within this review, it is more likely that they will be effective at reducing acute hospital events. PROSPERO registration number CRD42020142523.
Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II

PURPOSE The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL. GROINSS-V-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy in vulvar cancer patients with a metastatic sentinel node. This study included 1535 eligible patients of whom 322 (21.0%) had SN metastases. The results show that inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN-micrometastases (=2 mm), with minimal morbidity and a groin recurrence rate of 1.6% at 2 years. For patients with SN-macrometastasis (>2 mm), radiotherapy with a total dose of 50Gy resulted in more isolated groin recurrences compared to IFL.
Personality Traits and Urinary Symptoms Are Associated with Mental Health Distress in Patients with a Diagnosis of Prostate Cancer

Objective: With a prolonged natural history compared with many other cancers, prostate cancer patients have high rates of mental illness over the duration of their treatment. Here, we examine the relationship between personality and mental health distress in a sample of prostate cancer patients. Methods: This study was conducted in the Canadian Maritime provinces, where a cohort of 189 men with prostate cancer were invited to complete a quality-of-life online survey between May 2017 and December 2019. The presence or absence of screening positive for mental health illness was the primary outcome and was assessed using Kessler’s 10-item scale (K10). Urinary symptoms were assessed using the International Prostate Symptom Score (IPSS). The ten-item personality inventory (TIPI) assessed extraversion, agreeableness, conscientiousness, emotional stability (or neuroticism), and openness to experiences. A multivariate logistic regression model was created to examine the association between personality, urinary symptoms, and mental health distress, while controlling for time from diagnosis, treatment type, age, and multimorbidity. Results: Screening positive for mental illness (18.0%) was associated with personality traits of low levels of emotional stability (OR = 0.07, 95% CI: 0.03–0.20) and moderate to severe urinary problems (OR = 5.21, 95% CI: 1.94–14.05)). There was no identified association between treatment received for prostate cancer and personality type. Conclusion: Screening for mental health illness in this population may help reduce morbidity associated with cancer treatment, as well as identify patients who may be at risk of mental health distress and could benefit from individualized mental health support services. These findings suggest that multidisciplinary care is essential for the management of these patients.
Behavior of Children during Dental Care with Rubber Dam Isolation: A Randomized Controlled Study

Background: The establishment of the dental dam improves dentist working conditions and patient protection. The purpose of this study was to analyze the behavior of the child during dental care with or without a dam. Methods: In this interventional randomized study, 51 patients are divided into two groups, one with a rubber dam and the other with cotton roll isolation. Their behavior was observed during the treatment of temporary molars. The duration of the treatment, the patient’s feeling with a visual analogue scale (VAS), the behavior (B) of the child measured with a hetero-evaluation scale (modified Venham scale) and the cardiac frequency (CF) were measured. Results: The group treated with a rubber dam has a significant decrease in the various stress parameters that have been identified (B, p value = 0.034; CF, p value = 0.015). Subgroups of patients with and without nitrous oxide sedation were compared and similar results were obtained. Conclusions: Isolation with a rubber dam reduces child’s stress during dental care. Although it is slightly more time-consuming and training is necessary for a quick and effective placement, it allows dentists to perform dental care in the best possible conditions, while reducing dental anxiety in young patients.
Protective Effect of Nigella sativa and Nigella damascena Fixed Oils Against Aflatoxin Induced Mutagenicity in the Classical and Modified Ames Test

The antioxidant and mutagenic/antimutagenic activities of the fixed oils from Nigella sativa (NSO) and Nigella damascena (NDO) seeds, obtained by cold press‐extraction from the cultivar samples, were comparatively investigated for the first time. The antimutagenicity test was carried out using classical and modified Ames tests. The fatty acid composition of the fixed oils was characterized by gas chromatography–mass spectrometry (GC‐MS) while the quantification of thymoquinone in the fixed oils was determined by UPC2. The main components of the NSO and NDO were found to be linoleic acid, oleic acid, and palmitic acid. The results of the Ames test confirmed the safety of NSO and NDO from the viewpoint of mutagenicity. The results of the three antioxidant test methods were correlated with each other, indicating NDO as having a superior antioxidant activity, when compared to the NSO. Both NSO and NDO exhibited a significant protective effect against the mutagenicity induced by aflatoxin B1 in Salmonella typhimurium TA98 and TA100 strains. When microsomal metabolism was terminated after metabolic activation of the mycotoxin, a significant increase in antimutagenic activity was observed, suggesting that the degradation of aflatoxin B1 epoxides by these oils may be a possible antimutagenic mechanism. It is worthy to note that this is the first study to assess the mutagenicity of NSO and NDO according to the OECD 471 guideline and to investigate antimutagenicity of NDO in comparison to NSO against aflatoxin.
Prospects for daily online adaptive radiotherapy via ethos for prostate cancer patients without nodal involvement using unedited CBCT auto‐segmentation

Abstract Purpose Implementing new online adaptive radiation therapy technologies is challenging because extra clinical resources are required particularly expert contour review. Here, we provide the first assessment of Varian's Ethos™ adaptive platform for prostate cancer using no manual edits after auto‐segmentation to minimize this impact on clinical efficiency. Methods Twenty‐five prostate patients previously treated at our clinic were re‐planned using an Ethos™ emulator. Clinical target volumes (CTV) included intact prostate and proximal seminal vesicles. The following clinical margins were used: 3 mm posterior, 5 mm left/right/anterior, and 7 mm superior/inferior. Adapted plans were calculated for 10 fractions per patient using Ethos's auto‐segmentation and auto‐planning workflow without manual contouring edits. Doses and auto‐segmented structures were exported to our clinical treatment planning system where contours were modified as needed for all 250 CTVs and organs‐at‐risk. Dose metrics from adapted plans were compared to unadapted plans to evaluate CTV and OAR dose changes. Results Overall 96% of fractions required auto‐segmentation edits, although corrections were generally minor (<10% of the volume for 70% of CTVs, 88% of bladders, and 90% of rectums). However, for one patient the auto‐segmented CTV failed to include the superior portion of prostate that extended into the bladder at all 10 fractions resulting in under‐contouring of the CTV by 31.3% ± 6.7%. For the 24 patients with minor auto‐segmentation corrections, adaptation improved CTV D98% by 2.9% ± 5.3%. For non‐adapted fractions where bladder or rectum V90% exceeded clinical thresholds, adaptation reduced them by 13.1% ± 1.0% and 6.5% ± 7.3%, respectively. Conclusion For most patients, Ethos's online adaptive radiation therapy workflow improved CTV D98% and reduced normal tissue dose when structures would otherwise exceed clinical thresholds, even without time‐consuming manual edits. However, for one in 25 patients, large contour edits were required and thus scrutiny of the daily auto‐segmentation is necessary and not all patients will be good candidates for adaptation.