Miracle-dz/UniFAR-FTUs huggingface dataset:
Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy.

Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from non-responders shortly following treatment and identified acute IFN-γ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot.
Prospective Surveillance of Primary Healthcare Presentations for Scabies and Bacterial Skin Infections in Fiji, 2018-2019.

Scabies, impetigo, and other skin and soft tissue infections (SSTIs) are highly prevalent in many tropical, low-middle income settings, but information regarding their burden of disease is scarce. We conducted a surveillance of presentations of scabies and SSTIs, including impetigo, abscesses, cellulitis, and severe SSTI, to primary health facilities in Fiji. We established a monthly reporting system over the course of 50 weeks (July 2018-June 2019) for scabies and SSTIs at all 42 public primary health facilities in the Northern Division of Fiji (population, ≈131,914). For each case, information was collected regarding demographics, diagnosis, and treatment. There were 13,736 individual primary healthcare presentations with scabies, SSTI, or both (108.3 presentations per 1000 person-years; 95% confidence interval [CI], 106.6-110 presentations). The incidence was higher for males than for females (incidence rate ratio [IRR], 1.15; 95% CI, 1.11-1.19). Children younger than 5 years had the highest incidence among all age groups (339.1 per 1000 person-years). The incidence was higher among the iTaukei (indigenous) population (159.9 per 1000 person-years) compared with Fijians of Indian descent (30.1 per 1000 person-years; IRR, 5.32; 95% CI, 5.03-5.61). Abscesses had the highest incidence (63.5 per 1,000 person-years), followed by scabies (28.7 per 1,000 person-years) and impetigo (21.6 per 1,000 person-years). Scabies and SSTIs impose a substantial burden in Fiji and represent a high incidence of primary health presentations in this population. The incidence in low-middle income settings is up to 10-times higher than that in high-income settings. New public health strategies and further research are needed to address these conditions.
Rasch validation and comparison of the German versions of the Locomotor Capabilities Index-5 and Prosthetic Mobility Questionnaire 2.0 in lower-limb prosthesis users

This study aimed to compare, through Rasch analysis, the psychometric properties of the Locomotor Capabilities Index (LCI-5) and Prosthetic Mobility Questionnaire (PMQ 2.0) in German lower-limb prosthesis users. The questionnaires were concurrently administered to a convenience sample of 98 consecutively recruited individuals with lower limb amputation (LLA) (male/female = 61/37; mean age 57 ± 14 years). LCI-5 showed disordered rating scale thresholds (one response option in three items required collapsing); local dependence between two items (resolved by creating a testlet); underfit of one item (‘Get up from the floor’); and presence of a second weak dimension. PMQ 2.0 showed a correctly functioning rating scale; good fit of the data to the model (apart from some overfit); local dependence between two items (absorbed by creating a testlet); and essential unidimensionality. At scale co-calibration onto a common interval-scaled metric, PMQ 2.0 was better targeted than LCI-5 (i.e. the extent of item difficulty was more appropriate for the sample) and its operational range allowed a more precise measurement of higher locomotor abilities. The correlation between LCI-5 and PMQ 2.0 scores was rho = 0.78. In conclusion, LCI-5 revealed some drawbacks, confirming a previous Rasch study; refinement of its rating scale and item selection seems therefore warranted. The PMQ 2.0 demonstrated good overall measurement quality, in line with previous Italian and Slovene studies. The operational range of the PMQ 2.0 makes it more suitable than LCI-5 for assessing people with high locomotor abilities.
Cellular and humoral response after MRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients

According to preliminary data, seroconversion after mRNA SARS‐CoV‐2 vaccination might be unsatisfactory in Kidney Transplant Recipients (KTRs). However, it is unknown if seronegative patients develop at least a cellular response that could offer a certain grade of protection against SARS‐CoV‐2. To answer this question, we prospectively studied 148 recipients of either kidney (133) or kidney‐pancreas (15) grafts with assessment of IgM/IgG spike (S) antibodies and ELISpot against the nucleocapside (N) and the S protein at baseline and 2 weeks after receiving the second dose of the mRNA‐1273 (Moderna) vaccine. At baseline, 31 patients (20.9%) had either IgM/IgG or ELISpot positivity and were considered to be SARS‐CoV‐2‐pre‐immunized, while 117 (79.1%) patients had no signs of either cellular or humoral response and were considered SARS‐CoV‐2‐naïve. After vaccination, naïve patients who developed either humoral or cellular response were finally 65.0%, of which 29.9% developed either IgG or IgM and 35.0% S‐ELISpot positivity. Factors associated with vaccine unresponsiveness were diabetes and treatment with antithymocytes globulins during the last year. Side effects were consistent with that of the pivotal trial and no DSAs developed after vaccination. In conclusion, mRNA‐1273 SARS‐CoV‐2 vaccine elicits either cellular or humoral response in almost two thirds of KTRs.
Self-Perceived Health and Chronic Conditions Among Users of Supplements With and Without Botanical Ingredients: Findings from the 2009–2014 National Health and Nutrition Examination Survey

Abstract The objective of this research was to investigate associations among self-reported health status, chronic conditions, and use of dietary supplements containing botanicals and describe reasons for use among U.S. adult supplement users. This was a cross-sectional analysis using data from the 2009–2014 National Health and Nutrition Examination Survey (NHANES). Supplement information was collected with a 30-day recall interview. Self-reported general health status and doctor-informed diagnoses of chronic conditions were assessed using a health status questionnaire. We used weighted multivariate logistic regressions to assess associations between supplement use and perceived health and number of chronic conditions. Participants were 16,958 non-institutionalized U.S. adults aged 20 years and older. Adults with excellent or very good self-perceived health were more likely to use botanical supplements than adults with good perceived health (adjusted odds ratio [aOR], 1.48; 95% confidence interval [CI], 1.28–1.74). Adults with three or more chronic conditions were more likely to report using botanical supplements than adults with no chronic conditions (aOR, 1.49; 95% CI, 1.13–1.69). The most frequently reported reasons for both non-botanical and botanical supplements use were “personal choice or influenced by advertisements or word of mouth,” “improve health,” and “specific health conditions” (93.3%, 84.2%, and 64.7%, respectively). While perceptions of health are more positive among adults using botanical supplements, chronic conditions and reasons for botanical supplements use related to personal choice, improving health, or addressing specific conditions were more likely. Differentiating botanical supplements from other complementary and integrative therapies may be useful for facilitating a deeper understanding of the reasons.
Preoperative embolization of jugular paraganglioma tumors using particles is safe and effective

Background Jugular paragangliomas represent a surgical challenge due to their vascularity and proximity to vital neurovascular structures. Preoperative embolization aids in reducing intraoperative blood loss, transfusion requirements, and improves surgical visualization. Several embolization agents have been used. Objective The aim of this study is to evaluate the safety and efficacy of PVA in pre-operative embolization of jugular paragangliomas. Methods A retrospective review of all patients who underwent jugular paraganglioma resection with pre-operative embolization between 2000 and 2020 was performed. Pre-operative data including baseline patient and tumor characteristics were documented. Outcomes of preoperative embolization including extent of devascularization and post-embolization complications were recorded. Early and long-term postoperative outcomes were reported. Results Twenty-nine patients met study criteria with a median age of 38 years. Average tumor size was 3.4±1.8 cm. The most commonly encountered arterial feeder was the ascending pharyngeal artery followed by the posterior auricular artery. More than 50% reduction in tumor blush was achieved in 25 patients (86.2%). None of the patients experienced new or worsening cranial neuropathy following embolization. Gross total or Near total resection was achieved in 13 patients (44.8%). A STR or NTR was chosen in these patients to preserve cranial nerve function or large vessel integrity. Average intraoperative estimated blood loss was 888 ml, 9 patients (31%) required intra-operative transfusion of blood products. Extent of resection and post-operative complications did not correlate with extent of devascularization. Conclusion Pre-operative embolization of jugular paraganglioma tumors with PVA particles is an effective strategy with a high safety profile.
Effects of orthodontic treatment with aligners and fixed appliances on speech.

OBJECTIVES To evaluate effects of orthodontic treatment with aligners and conventional fixed appliances on production of speech. MATERIALS AND METHODS This was a parallel, randomized clinical trial. Patients with Angle Class I malocclusion, moderate crowding, and no speech impairment were randomly allocated to two groups: patients with orthodontic aligners (OAs; n = 20; mean age = 23.60 ± 5.65 years) and those with conventional fixed appliances (n = 20; mean age = 20.56 ± 4.51 years) and treated at the University of North Parana's clinic in Londrina, Brazil. Evaluation of speech production was performed semiobjectively by a speech therapist (myofunctional orofacial examination) and subjectively (self-assessment) at five time points: baseline, immediately after insertion of appliances, and subsequently at 3, 30, and 180 days after insertion. For intergroup comparison, independent t, χ2, Fisher exact, and Mann-Whitney tests were used; for intragroup comparison, the Friedman test was applied (α = 5%). RESULTS In the semiobjective evaluation, patients with OAs exhibited a change in production of speech production, compared with patients with fixed appliances, immediately and 3 days after insertion of appliances (P < .001). Thirty days after insertion, the groups were similar (P = .487), an outcome that was unchanged at 180 days. However, in the self-assessments, patients in both groups reported significant speech difficulties immediately and 3 days after insertion of appliances, but such impairment was no longer perceived at 30 days or 180 days. CONCLUSIONS Although the speech therapist identified changes in speech production at the start of treatment in the OA group only, patient self-assessments demonstrated that orthodontic treatment, regardless of the type of appliance used, interfered with their perception of speech.
The usefulness of a hydrolysed fish and rice starch elimination diet for the diagnosis of adverse food reactions in cats: an open clinical trial

Background Diagnosis of adverse food reaction (AFR) is based on an eight week elimination diet (ED) and is confirmed by relapse upon re‐challenge with the previously fed diet. Hydrolysed EDs are commonly used for this purpose. Objective To evaluate the commercially available hydrolysed fish protein and rice starch ED Farmina UltraHypo (FUH) for the diagnosis of feline AFR. Animals Thirty‐two nonseasonally pruritic cats. Methods and materials Pruritus was assessed with a new dual Visual Analog Scale, lesions with the Scoring Feline Allergic Dermatitis scale and Quality of Life with a validated questionnaire on days 0 and 56. Short‐acting corticosteroids or oclacitinib were permitted during the first six weeks. Cats showing 50% pruritus and/or lesional improvement were separately challenged with their prior diet, fish and rice. Cats not responding to the study diet were fed another hydrolysed diet for two months. Results Twenty‐five cats completed the ED: four dropped out due to vomiting and/or diarrhoea, one owing to low palatability and two were lost to follow‐up. In 17 cats, pruritus improved by >50% and these underwent dietary challenges. Of these, nine reacted to their prior diet and/or fish and/or rice and were diagnosed with AFR, while eight did not relapse (and a diagnosis of AFR was considered to be doubtful). Of the eight cats in which pruritus did not improve, four underwent a second ED with no improvement. Conclusion and clinical importance FUH may be a useful ED for the diagnosis of feline AFR, even in cats reacting to fish or rice.
Spatio-Temporal-Spectral Hierarchical Graph Convolutional Network With Semisupervised Active Learning for Patient-Specific Seizure Prediction

Graph theory analysis using electroencephalogram (EEG) signals is currently an advanced technique for seizure prediction. Recent deep learning approaches, which fail to fully explore both the characterizations in EEGs themselves and correlations among different electrodes simultaneously, generally neglect the spatial or temporal dependencies in an epileptic brain and, thus, produce suboptimal seizure prediction performance consequently. To tackle this issue, in this article, a patient-specific EEG seizure predictor is proposed by using a novel spatio-temporal-spectral hierarchical graph convolutional network with an active preictal interval learning scheme (STS-HGCN-AL). Specifically, since the epileptic activities in different brain regions may be of different frequencies, the proposed STS-HGCN-AL framework first infers a hierarchical graph to concurrently characterize an epileptic cortex under different rhythms, whose temporal dependencies and spatial couplings are extracted by a spectral-temporal convolutional neural network and a variant self-gating mechanism, respectively. Critical intrarhythm spatiotemporal properties are then captured and integrated jointly and further mapped to the final recognition results by using a hierarchical graph convolutional network. Particularly, since the preictal transition may be diverse from seconds to hours prior to a seizure onset among different patients, our STS-HGCN-AL scheme estimates an optimal preictal interval patient dependently via a semisupervised active learning strategy, which further enhances the robustness of the proposed patient-specific EEG seizure predictor. Competitive experimental results validate the efficacy of the proposed method in extracting critical preictal biomarkers, indicating its promising abilities in automatic seizure prediction.
Professional quality of life, self‐compassion, resilience, and empathy in healthcare professionals during COVID‐19 crisis in Spain

Abstract The coronavirus pandemic has exposed healthcare professionals to suffering and stressful working conditions. The aim of this study was to analyze professional quality of life among healthcare professionals and its relationship with empathy, resilience, and self‐compassion during the COVID‐19 crisis in Spain. A cross‐sectional study was conducted with 506 healthcare professionals, who participated by completing an online questionnaire. A descriptive correlational analysis was performed. A multivariate regression analysis and a decision tree were used to identify the variables associated with professional quality of life. Empathy, resilience, and mindfulness were the main predictors of compassion fatigue, compassion satisfaction, and burnout, respectively.
CAVA (Ultrasound‐Accelerated Catheter‐Directed Thrombolysis on Preventing Post‐Thrombotic Syndrome) Trial: Long‐Term Follow‐Up Results

Background The CAVA (Ultrasound‐Accelerated Catheter‐Directed Thrombolysis Versus Anticoagulation for the Prevention of Post‐Thrombotic Syndrome) trial did not show a reduction of post‐thrombotic syndrome (PTS) after additional ultrasound‐accelerated catheter‐directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1‐year follow‐up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long‐term follow‐up. Methods and Results Patients aged 18 to 85 years with a first‐time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound‐accelerated catheter‐directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow‐up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow‐up of 39.0 months (interquartile range, 23.3–63.8), 120 patients (79.8%) participated in the final follow‐up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of −14.2% (95% CI, −32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19–0.84 [P=0.01]) with an absolute difference between groups of −22.2% (95% CI, −39.8% to −2.8%). No new major bleedings occurred following the 12‐month follow‐up. Conclusions The impact of additional ultrasound‐accelerated catheter‐directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials. gov; Unique identifier: NCT00970619.
Optimized alginate-based 3D printed scaffolds as a model of patient derived breast cancer microenvironments in drug discovery

The cancer microenvironment influences tumor progression and metastasis and is pivotal to consider when designing in vivo-like cancer models. Current preclinical testing platforms for cancer drug development are mainly limited to 2D cell culture systems that poorly mimic physiological environments and traditional, low throughput animal models. The aim of this work was to produce a tunable testing platform based on 3D printed scaffolds (3DPS) with a simple geometry that, by extracellular components and response of breast cancer reporter cells, mimics patient-derived scaffolds (PDS) of breast cancer. Here, the biocompatible polysaccharide alginate was used as base material to generate scaffolds consisting of a 3D grid containing periostin and hydroxyapatite. Breast cancer cell lines (MCF7 and MDA-MB-231) produced similar phenotypes and gene expression levels of cancer stem cell, epithelial–mesenchymal transition, differentiation and proliferation markers when cultured on 3DPS and PDS, contrasting conventional 2D cultures. Importantly, cells cultured on 3DPS and PDS showed scaffold-specific responses to cytotoxic drugs (doxorubicin and 5-fluorouracil) that were different from 2D cultured cells. In conclusion, the data presented support the use of a tunable alginate-based 3DPS as a tumor model in breast cancer drug discovery.
Lichen Depsidones with Biological Interest

Abstract Depsidones are some of the most abundant secondary metabolites produced by lichens. These compounds have aroused great pharmacological interest due to their activities as antioxidants, antimicrobial, and cytotoxic agents. Hence, this paper aims to provide up-to-date knowledge including an overview of the potential biological interest of lichen depsidones. So far, the most studied depsidones are fumarprotocetraric acid, lobaric acid, norstictic acid, physodic acid, salazinic acid, and stictic acid. Their pharmacological activities have been mainly investigated in in vitro studies and, to a lesser extent, in in vivo studies. No clinical trials have been performed yet. Depsidones are promising cytotoxic agents that act against different cell lines of animal and human origin. Moreover, these compounds have shown antimicrobial activity against both Gram-positive and Gram-negative bacteria and fungi, mainly Candida spp. Furthermore, depsidones have antioxidant properties as revealed in oxidative stress in vitro and in vivo models. Future research should be focused on further investigating the mechanism of action of depsidones and in evaluating new potential actions as well as other depsidones that have not been studied yet from a pharmacological perspective. Likewise, more in vivo studies are prerequisite, and clinical trials for the most promising depsidones are encouraged.
An Antigen Capture Assay for the Detection of Mycolactone, the Polyketide Toxin of Mycobacterium ulcerans

Key Points Sets of mAbs specific for the macrolide toxin mycolactone have been generated. Two selected mAbs enabled development of a highly sensitive capture ELISA. The assay has potential for conversion into a rapid diagnostic test for Buruli ulcer. Mycolactone is a cytotoxin responsible for most of the chronic necrotizing pathology of Mycobacterium ulcerans disease (Buruli ulcer). The polyketide toxin consists of a 12-membered lactone ring with a lower O-linked polyunsaturated acyl side chain and an upper C-linked side chain. Mycolactone is unique to M. ulcerans and an immunological Ag capture assay would represent an important tool for the study of Buruli ulcer pathogenesis and for laboratory diagnosis. When testing sets of mycolactone-specific mouse mAbs, we found that Abs against the hydrophobic lower side chain only bind mycolactone immobilized on a solid support but not when present in solution. This observation supports previous findings that mycolactone forms micellar structures in aqueous solution with the hydrophobic region sequestered into the inner core of the aggregates. Although an Ag capture assay typically requires two Abs that recognize nonoverlapping epitopes, our search for matching pairs of mAbs showed that the same mAb could be used both as capture and as detecting reagent for the detection of the mycolactone aggregates. However, the combination of a core-specific and a core/upper side chain–specific mAb constituted the most sensitive ELISA with a sensitivity in the low nanogram range. The results of a pilot experiment showed that the sensitivity of the assay is sufficient to detect mycolactone in swab samples from Buruli ulcer lesions. Although the described capture ELISA can serve as a tool for research on the biology of mycolactone, the assay system will have to be adapted for use as a diagnostic tool.