Miracle-dz/UniFAR-FTUs huggingface dataset:
Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

PURPOSE Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
Sequence-to-Segments Networks for Detecting Segments in Videos

Detecting segments of interest from videos is a common problem for many applications. And yet it is a challenging problem as it often requires not only knowledge of individual target segments, but also contextual understanding of the entire video and the relationships between the target segments. To address this problem, we propose the Sequence-to-Segments Network (S2N), a novel and general end-to-end sequential encoder-decoder architecture. S2N first encodes the input video into a sequence of hidden states that capture information progressively, as it appears in the video. It then employs the Segment Detection Unit (SDU), a novel decoding architecture, that sequentially detects segments. At each decoding step, the SDU integrates the decoder state and encoder hidden states to detect a target segment. During training, we address the problem of finding the best assignment of predicted segments to ground truth using the Hungarian Matching Algorithm with Lexicographic Cost. Additionally we propose to use the squared Earth Mover's Distance to optimize the localization errors of the segments. We show the state-of-the-art performance of S2N across numerous tasks, including video highlighting, video summarization, and human action proposal generation.
Clinicopathologic Association and Prognostic Value of MELF Pattern in Invasive Endocervical Adenocarcinoma (ECA) as Classified by IECC

Microcystic, elongated, and fragmented (MELF) pattern of myometrial invasion is correlated with lymphovascular invasion (LVI) and lymph node metastases in uterine endometrioid carcinoma but has not been described in endocervical adenocarcinoma (ECA). A total of 457 ECAs were collected, and clinical/morphologic parameters correlated with follow-up data. Potential associations between MELF pattern and age, human papillomavirus status, tumor size/grade, LVI, lymph node metastases, Silva pattern were analyzed. Statistical analyses of overall survival (OS), disease-free survival, progression-free survival (PFS) were conducted using Kaplan-Meier analysis, and compared using the Log-rank test. Of 292 ECAs analyzed, 94 (32.19%) showed MELF invasion pattern (MELF-positive). Significant statistical correlation was found between MELF-positive and tumor size (P=0.0017), LVI (P=0.007), Silva pattern (P=0.0005); age, human papillomavirus status, tumor grade, lymph node metastases did not correlate. Fifty-five of 292 patients recurred (18.83%): 18/94 (19.14%) MELF-positive, 37/198 (18.68%) MELF-negative. PFS in MELF-positive: 77.2% and 64.5% at 5 and 10 yr, respectively; PFS in MELF-negative: 82% and 68.5% at 5 and 10 yr, respectively. On multivariate analysis for PFS and other prognostic parameters, only LVI was statistically significant (P=0.001). OS in MELF-positive was 86% and 74.1% at 5 and 10 yr, respectively; OS in MELF-negative, was 89.7% and 86% at 5 and 10 yr, respectively. Median survival was worse in MELF-positive (199.8 mo) versus MELF-negative (226.1 mo); this was not statistically significant. On multivariate analysis for OS and other prognostic parameters, only tumor stage was statistically significant (P=0.002). In ECAs, MELF is not independently associated with survival. Pathologic characteristics of MELF-positive (size, LVI, Silva pattern) versus MELF-negative tumors differ significantly.
Organisational and financial consequences of the early discharge of patients treated for acute bacterial skin and skin structure infection and osteomyelitis in infectious disease departments in Greece, Italy and Spain: a scenario analysis

Objective The aim of the analysis is to assess the organisational and economic consequences of adopting an early discharge strategy for the treatment of acute bacterial skin and skin structure infection (ABSSSI) and osteomyelitis within infectious disease departments. Setting Infectious disease departments in Greece, Italy and Spain. Participants No patients were involved in the analysis performed. Interventions An analytic framework was developed to consider two alternative scenarios: standard hospitalisation care or an early discharge strategy for patients hospitalised due to ABSSSI and osteomyelitis, from the perspective of the National Health Services of Greece, Italy and Spain. The variables considered were: the number of annual hospitalisations eligible for early discharge, the antibiotic treatments considered (ie, oral antibiotics and intravenous long-acting antibiotics), diagnosis-related group (DRG) reimbursements, number of days of hospitalisation, incidence and costs of hospital-acquired infections, additional follow-up visits and intravenous administrations. Data were based on published literature and expert opinions. Primary and secondary outcome measures Number of days of hospitalisation avoided and direct medical costs avoided. Results The total number of days of hospitalisation avoided on a yearly basis would be between 2216 and 5595 in Greece (−8/−21 hospital beds), between 15 848 and 38 444 in Italy (−57/−135 hospital beds) and between 7529 and 23 520 in Spain (−27/−85 hospital beds). From an economic perspective, the impact of the early discharge scenario is a reduction between €45 036 and €149 552 in Greece, a reduction between €182 132 and €437 990 in Italy and a reduction between €292 284 and €884 035 in Spain. Conclusions The early discharge strategy presented would have a positive organisational impact on National Health Services, leading to potential savings in beds, and to a reduction of hospital-acquired infections and costs.
Characteristics of diabetic macular edema patients refractory to anti-VEGF treatments and a dexamethasone implant

Purpose To determine the characteristics of diabetic macular edema (DME) patients refractory to intravitreal bevacizumab (IVB) treatments and an additional dexamethasone implant. Methods We classified 119 DME patients according to whether or not they are responsive to 3 consecutive monthly anti-VEGF treatments and/or an additional dexamethasone implant. We compared their concentrations of IL (interleukin)-1β, IL-8, IL-10, IL-17, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) in the aqueous humor as well as their optical coherence tomography (OCT) findings, and baseline characteristics. We used logistic regression analyses to identify preoperative factors related to refractoriness to treatments. Results Of 119 treatment-naïve DME patients, 50 (42.02%) patients showed responsiveness [central subfield thickness (CST) < 300μm] after 3 IVBs, and 59 (49.58%) patients showed responsiveness after an additional dexamethasone implant, but 10 (8.40%) patients showed CST 300 ≥ μm even after both treatments. Refractory DME patients showed significantly higher number of hyperreflective foci (HF) in the OCT and higher average level of aqueous IL-1β at baseline (p<0.001 and p = 0.042, respectively). In the logistic regression analysis, higher number of HF in the OCT was associated with the refractoriness to both treatments (odds ratio [OR]: 7.03, p = 0.007) Conclusions Higher number of HF in the OCT at the initial visit was associated with poor responses to IVBs and an additional dexamethasone implant.
Randomized Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcoma: A Report From the Children's Oncology Group.

PURPOSE The primary aim of this clinical trial was to prioritize bevacizumab or temsirolimus for additional investigation in rhabdomyosarcoma (RMS) when administered in combination with cytotoxic chemotherapy to patients with RMS in first relapse with unfavorable prognosis. PATIENTS AND METHODS Patients were randomly assigned to receive bevacizumab on day 1 or temsirolimus on days 1, 8, and 15 of each 21-day treatment cycle, together with vinorelbine on days 1 and 8, and cyclophosphamide on day 1 for a maximum of 12 cycles. Local tumor control with surgery and/or radiation therapy was permitted after 6 weeks of treatment. The primary end point was event-free survival (EFS). Radiographic response was assessed at 6 weeks. The study had a phase II selection that was design to detect a 15% difference between the two regimens (α = .2; 1-β = 0.8; two sided test). RESULTS Eighty-seven of 100 planned patients were enrolled when the trial was closed after the second interim analysis after 46 events occurred in 68 patients with sufficient follow-up. The O'Brien Fleming boundary at this analysis corresponded to a two-sided P value of . 058 with an observed two-sided P value of . 003 favoring temsirolimus. The 6-month EFS for the bevacizumab arm was 54.6% (95% CI, 39.8% to 69.3%) and 69.1% (95% CI, 55.1% to 83%) for the temsirolimus arm. Objective response rates were 28% (95% CI, 13.7% to 41.3%) and 47% (95% CI, 31.5% to 63.2%) for the bevacizumab and temsirolimus arms, respectively (P = .12) and, 28% of patients on bevacizumab and 11% on temsirolimus had progressive disease at 6 weeks. CONCLUSION Patients who received temsirolimus had a superior EFS compared with bevacizumab. Temsirolimus has been selected for additional investigation in newly diagnosed patients with intermediate-risk RMS.
Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.
Development of a High-Throughput Fluorescence Polarization Assay to Detect Inhibitors of the FAK–Paxillin Interaction

Focal adhesion kinase (FAK) is a promising cancer drug target due to its massive overexpression in multiple solid tumors and its critical role in the integration of signals that control proliferation, invasion, apoptosis, and metastasis. Previous FAK drug discovery and high-throughput screening have exclusively focused on the identification of inhibitors that target the kinase domain of FAK. Because FAK is both a kinase and scaffolding protein, the development of novel screening assays that detect inhibitors of FAK protein–protein interactions remains a critical need. In this report, we describe the development of a high-throughput fluorescence polarization (FP) screening assay that measures the interactions between FAK and paxillin, a focal adhesion–associated protein. We designed a tetramethylrhodamine (TAMRA)-tagged paxillin peptide based on the paxillin LD2 motif that binds to the focal adhesion targeting (FAT) domain with significant dynamic range, specificity, variability, stability, and a Z’-factor suitable for high-throughput screening. In addition, we performed a pilot screen of 1593 compounds using this FP assay, showing its feasibility for high-throughput drug screening. Finally, we identified three compounds that show dose-dependent competition of FAT–paxillin binding. This assay represents the first described high-throughput screening assay for FAK scaffold inhibitors and can accelerate drug discovery efforts for this promising drug target.
Direct electrical stimulation mapping of cognitive functions in the human brain

ABSTRACT Direct electrical stimulation (DES) is a well-established clinical tool for mapping cognitive functions while patients are undergoing awake neurosurgery or invasive long-term monitoring to identify epileptogenic tissue. Despite the proliferation of a range of invasive and noninvasive methods for mapping sensory, motor and cognitive processes in the human brain, DES remains the clinical gold standard for establishing the margins of brain tissue that can be safely removed while avoiding long-term neurological deficits. In parallel, and principally over the last two decades, DES has emerged as a powerful scientific tool for testing hypotheses of brain organization and mechanistic hypotheses of cognitive function. DES can cause transient “lesions” and thus can support causal inferences about the necessity of stimulated brain regions for specific functions, as well as the separability of sensory, motor and cognitive processes. This Special Issue of Cognitive Neuropsychology emphasizes the use of DES as a research tool to advance understanding of normal brain organization and function.
Comparative compositional and functional analyses of Bothrops moojeni specimens reveal several individual variations

Snake venoms are complex protein mixtures with different biological activities that can act in both their preys and human victims. Many of these proteins play a role in prey capture and in the digestive process of these animals. It is known that some snakes are resistant to the toxicity of their own venom by mechanisms not yet fully elucidated. However, it was observed in the Laboratory of Herpetology of Instituto Butantan that some Bothrops moojeni individuals injured by the same snake species showed mortalities caused by envenoming effects. This study analyzed the biochemical composition of 13 venom and plasma samples from Bothrops moojeni specimens to assess differences in their protein composition. Application of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) showed distinct venom protein profiles, but very homogeneous plasma profiles. Western Blotting (WB) was performed with plasma samples, which were submitted to incubation with the respective venom. Some individuals showed an immunorecognized band zone around 25 kDa, indicating interaction between the same individual plasma and venom proteins. Crossed-WB assay using non-self-plasma and venom showed that this variability is due to venom protein composition instead of plasma composition. These venoms presented higher caseinolytic, collagenolytic and coagulant activities than the venoms without these regions recognized by WB. Mass spectrometry analyses performed on two individuals revealed that these individuals present, in addition to higher protein concentrations, other exclusive proteins in their composition. When these same two samples were tested in vivo, the results also showed higher lethality in these venoms, but lower hemorrhagic activity than in the venoms without these regions recognized by WB. In conclusion, some Bothrops moojeni specimens differ in venom composition, which may have implications in envenomation. Moreover, the high individual venom variability found in this species demonstrates the importance to work with individual analyses in studies involving intraspecific venom variability and venom evolution.
A simple protocol to characterize bacterial cell‐envelope lipoproteins in a native‐like environment

Physiological conditions in living cells are strictly regulated to allow, optimize, and coordinate biological processes. The bacterial cell envelope is the compartment where the communication with the external environment takes place. This involves membrane proteins, key players in many biological processes that ensure bacterial survival. The biochemical characterization of membrane proteins, either integral, lipidated or peripheral is challenging due to their mixed protein‐lipid nature, making it difficult to purify and obtain considerable amounts of samples. In contrast to integral membrane proteins, lipidated proteins are usually purified as truncated soluble versions, neglecting the impact of the membrane environment. Here we report a simple and robust protocol to characterize bacterial lipidated proteins in spheroplasts from Escherichia coli using a β‐lactamase as a model. The Metallo‐β‐lactamase NDM‐1 is an enzyme anchored to the inner leaflet of the outer membrane of Gram‐negative bacteria. Kinetic parameters and stability of the lipidated NDM‐1 and the soluble unbound version (NDM‐1 C26A) were measured in spheroplasts and periplasm, respectively. These studies revealed that membrane anchoring increases the KM of the enzyme, consequently decreasing the catalytic efficiency, while not affecting its kinetic stability. This approach can be used to characterize lipidated proteins avoiding the purification step while mimicking its native environment. This approach also helps in filling the gap between in vitro and in vivo studies.
Searching for Health: Doctor Google and the Shifting Dynamics of the Middle-Aged and Older Adult Patient–Physician Relationship and Interaction

Objectives: While online health information (OHI) has become ubiquitous, little is known about its use by middle-aged and older adults. This contribution examines the role of OHI and its influence on the patient–physician relationship. Method: This qualitative study reports the thematic analysis of 40 semistructured, in-depth interviews with Flemish middle-aged and older adults between the ages of 50 and 80 years. Results: Middle-aged and older adults obtain OHI pre- and post-consultation, albeit with different motivations and in search of different types of information. Patients strategically and carefully introduce OHI in the clinical encounter. “Doctor Google” expands the traditional patient–physician dyad into an information triangle. Discussion: The findings have implications for policy guidance and clinical practice. Public campaigns against “Googling” for health information might have to be amended to be successful. Importantly, physicians are increasingly expected to refer to and appraise OHI and put it into the individual patient context.
Body composition and nutrition of female athletes

Background The somatic features of the athletes’ bodies partially determine their sporting level and are conditioned to a large extent by the state of nutrition. Objective The aim of this paper is to present nutritional status and its correlation with the somatic determinants of training athletes and physical education students. Material and methods This study involved 12 weightlifting players (subgroup-WL), 15 soccer players (subgroup-SP), 12 table tennis players (subgroup-TT) and 12 female students of physical education (subgroup-C). In all subjects, the age and somatic variables were recorded and the daily intake of energy, water, proteins, fats and carbohydrates was determined by 24-h dietary recalls. Results Although the analysis of variance did not show significant differences in somatic variables and nutrition data, post hoc analysis showed significant differences between some subgroups in terms of age, BMI, fat content (BF), fat-free mass (FFM) and the amount of water, protein and carbohydrates consumed during the day. It was also shown that somatic variables correlated with relatively expressed amounts of energy, proteins and carbohydrates consumed in individual subgroups, as well as in the whole group formed from all subgroups of studied women. In addition, there were significant correlations between somatic variables and the total amount of water consumed in the whole group and the total amount of protein consumed in subgroup C (p<0.05), as well as the total amount of fat consumed in subgroup WL. Conclusions In summary, it was found that the examined women used an abnormal hypoenergetic diet with too low carbohydrate content in which were more useful relative than absolute amounts of consumed proteins, fats and carbohydrates. In this unfavorable situation, dietary education of the respondents seems to be necessary.
Forced oscillation technique

Summary The forced oscillation technique (FOT) allows the characterisation of respiratorymechanics such as respiratory resistance (R rs ) and reactance (X rs ). The primaryadvantage of the FOT is that little active cooperation is needed from the subject andmeasurements are easily performed during tidal breathing with firm support of cheeksand mouth floor. Standards are available for equipment specifications and datacollection. Within-session variability should be documented, while between-sessionrepeatability is essential for the study of bronchomotor responses.Most clinically relevant information has been gained from R rs and/or X rs in thefrequency range 5–8 Hz, where R rs is mostly dependent on frictional losses in theairways and X rs is determined in great part by elastic respiratory properties. There hasbeen an increasing number of paediatric reports during the past decade, particularlyin uncooperative young children. Case–control studies have reported lung functionabnormalities in young children in chronic lung disease of prematurity, with lessconsistent data in cystic fibrosis. Findings in children with stable asthma appeardependent on inclusion criteria, with more abnormalities detected with recruitmentfrom asthma clinics than in field studies. Longitudinal studies in asthmatic childrenover weeks to months suggest the FOT and in particular X