Miracle-dz/UniFAR-FTUs huggingface dataset:
Immune Checkpoint Inhibitors for the Treatment of Unresectable Stage III Non–Small Cell Lung Cancer: Emerging Mechanisms and Perspectives

Abstract There has been no improvement in outcome for patients with unresectable locally advanced (stage III) non–small cell lung cancer (NSCLC) for more than 10 years. The standard treatment for these patients is definitive concurrent chemotherapy and radiation (CCRT). Although the goal of treatment in this setting is to achieve a cure, most patients progress and their prognosis is poor, with a 5-year survival rate of 15–30%. There is thus an urgent need for the development of novel anticancer treatments in this patient population. Recent advances in cancer immunotherapy have led to a marked improvement in clinical outcome for advanced NSCLC. Such immunotherapy mainly consists of the administration of immune checkpoint inhibitors (ICIs) such as antibodies to cytotoxic T lymphocyte–associated protein–4 (CTLA-4) or to either programmed cell death–1 (PD-1) or its ligand PD-L1. Durvalumab (MEDI4736) is a high-affinity human immunoglobulin G1 monoclonal antibody that blocks the binding of PD-L1 on tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population.
An Economic Analysis of Aneuploidy Screening of Oocytes in Assisted Reproduction in Germany

Background The randomized ESTEEM trial reported that preimplantation genetic aneuploidy testing of oocytes by polar body biopsy (PGT-A) with array comparative genomic hybridization (aCGH) in women aged 36 – 40 years undergoing assisted reproduction treatment reduces the number of embryo transfers and the risk of miscarriage while not impacting the live birth rate. Method A decision tree model based on data from the ESTEEM trial was created and analyzed, using three cost scenarios for assisted reproduction treatment in Germany (statutory health insurance [GKV] = the deductible is 50% of the standard medical costs; private medical insurance [PKV] = invoicing is based on the German medical fee schedule [GOÄ]; private medical insurance with a simple GOÄ factor [simple GOÄ factor] = invoicing is based on the standard medical fees multiplied by a linear GOÄ factor). The scenarios were compared for cost-effectiveness (cost per live birth), cost per prevented miscarriage and the threshold values for cost and effectiveness. Results PGT-A increased the costs per live birth in all scenarios (GKV: + 208%; PKV: + 49%; simple GOÄ factor: + 89%). A threshold analysis showed a substantial cost discrepancy between the actual cost of the intervention based on GOÄ (€ 5801) vs. the theoretically tolerable PGT-A cost (GKV: € 561, PKV: € 1037, single GOÄ-factor: € 743). The incremental cost per one prevented miscarriage was approximately € 70 000 – 75 000 for all cost scenarios. Conclusion The use of PGT-A with aCGH in assisted reproduction cannot be recommended from a cost-effectiveness perspective.
Recovering signals of ghost archaic introgression in African populations

Multiple West African populations inherited genes from a population that diverged before modern humans and Neanderthals split. While introgression from Neanderthals and Denisovans has been documented in modern humans outside Africa, the contribution of archaic hominins to the genetic variation of present-day Africans remains poorly understood. We provide complementary lines of evidence for archaic introgression into four West African populations. Our analyses of site frequency spectra indicate that these populations derive 2 to 19% of their genetic ancestry from an archaic population that diverged before the split of Neanderthals and modern humans. Using a method that can identify segments of archaic ancestry without the need for reference archaic genomes, we built genome-wide maps of archaic ancestry in the Yoruba and the Mende populations. Analyses of these maps reveal segments of archaic ancestry at high frequency in these populations that represent potential targets of adaptive introgression. Our results reveal the substantial contribution of archaic ancestry in shaping the gene pool of present-day West African populations.
CODEXS: A New Multidimensional Index to Better Predict Frequent COPD Exacerbators with Inclusion of Depression Score

Purpose Depression is reported in association with chronic obstructive pulmonary disease (COPD). However, to date, no multidimensional indices have taken depression into consideration to predict COPD patients’ prognosis. This study aimed to determine whether a new multidimensional index named CODEXS, based on comorbidities, airflow obstruction, dyspnea, previous exacerbation and depression assessed by Self-Rating Depression Scale (SDS), could predict 1-year exacerbations. Methods This was a prospective study, patients with stable COPD were used to develop CODEXS at the first visit, and followed up in the 3rd, 6th, and 12th months. After the last visit, patients were divided into frequent and infrequent exacerbators. Another cohort of COPD patients was used for validation. The SDS scoring system in the multidimensional indices ranged from 0 to 4 based on the modified SDS value, representing no depression (25–39 [0], 40–49 [1]), mild depression (50–59), moderate depression (60–69), and severe depression (≥70). Comorbidity, dyspnea, airflow obstruction, and severe exacerbations were calculated according to CODEX thresholds. Results Two sets of 105 and 107 patients were recruited in the development and validation cohorts, respectively. Depression was demonstrated as an independent risk factor for frequent exacerbators (odds ratio (OR)= 1.14, 95% confidence interval (CI) = 1.06–1.23, P < 0.001). The prevalence of depression in frequent exacerbators (35.09%) was higher than that in infrequent exacerbators. CODEXS was significantly associated with exacerbation (OR =2.91; 95% CI, 1.89–4.48, p<0.001). Receiver operating characteristic (ROC) curve comparison showed that CODEXS was superior to BODEX(BMI, airflow obstruction, dyspnea, previous exacerbation), BODE (BMI, airflow obstruction, dyspnea, exercise), and updated ADO (age, dyspnea, and airflow obstruction) indices, confirmed by the validation cohort with sensitivity at 85.94% and specificity at 76.74%. Conclusion Depression is an independent risk factor for COPD exacerbation. CODEXS is a useful predictor for predicting frequent exacerbators within 1 year and is superior to other previously published indices.
Prevalence and Associated Factors of Pterygium Among Adults Living in Kolla Diba Town, Northwest Ethiopia

Purpose: The aim of this study was to assess the prevalence and associated factors of pterygium among adults in Kolla Diba town, Northwest Ethiopia, 2019. Method: A community-based cross-sectional study was done in Kolla Diba town from May 30-June 16, 2019. A systematic random sampling technique was used to select 627 study participants. Data was collected through basic ophthalmic examination with a portable slit lamp, 3x magnifying loop and torchlight and a pretested structured questionnaire were administered to collect the data. Then the data entered into EPI INFO version 7 and analyzed using SPSS version 20. Descriptive statistics and binary logistic regression analysis were employed. P-values of <0.05 were considered statistically significant. Result: A total of 605 study participants were involved with a response rate of 96.5%. Among them 317 (52.4%) participants were males. The mean age of the respondents was 38.18 +/- 15.56 with a range of (18-95) in years. The overall Prevalence of pterygium among adults living in Kolla Diba town was 112 (18.5% (95% CI (15.6- 21.7)). Being widowed (AOR = 7.32 (95%CI: 2.88, 18.57)), outdoor occupation (AOR = 2.50 (95%CI: 1.46, 4.29)), sun exposure (AOR = 2.38 (95%CI: 1.28, 4.43)), wind exposure (AOR = 1.97 (95%CI: 1.04, 3.72)), alcohol drinking (AOR = 2.26 (95%CI: 1.48, 4.63)), and severe blepharitis (AOR = 2.45 (95%CI: 1.48, 4.05)) had statistically significant positive association with pterygium. Conclusion: The prevalence of pterygium was relatively higher. Marital status (being widowed), outdoor occupation, sun exposure, wind exposure, alcohol drinking, and severe blepharitis were significantly associated with the development of pterygium.
A Metabolomic Investigation of the Effect of Eosin B on Game-tocyte of Plasmodium falciparum Using 1HNMR Spectroscopy

Background: Recently eosin B was shown to have an effect on the asexual stage of Plasmodium falciparum and in this study, its activity against gametocytes and changes in the culture medium metabolites were investigated using an1HNMR-based metabolomics approach. Methods: In the Biochemistry Department of Pasteur Institute of Iran in 2017, parasites were cultured and gametocytogenesis induced by heparin and 5% hematocrit. Sexual stage parasites were tested by eosin B in 90 well plates and IC50 determined using Lactate Dehydrogenase assay. Gametocytes were treated by IC50 dose of eosin B and the medium collected in the two groups: with eosin B and controls and sent for 1HNMR spectroscopy. The spectra were analyzed on MATLAB interface and the altered metabolites in the culture medium and eosin-affected biochemical pathways were identified by Human Metabolome Database and Metabo-analyst website. Results: The results revealed eosin B had an effective gametocytocidal activity against P. falciparum. The significant metabolites changed in the medium were thia-mine, Asp, Asn, Tyr, Lys, Ala, Phenylpyruvic acid, NAD+ and lipids. The main pathways identified were aminoacyl-tRNA biosynthesis, Phenylalanine, tyrosine and tryptophan biosynthesis, Alanine, aspartate and glutamate metabolism, Phenylala-nine metabolism, Nicotinate and nicotinamide metabolism, and lysine degradation. Conclusion: Eosin B exhibited substantial gametocytocidal activity and affected important drug targets in the Plasmodium.
Memory Buttons in Combination with Mobile Application-Induced Objective and Subjective Effects in Patients with Atopic Dermatitis

Background Atopic dermatitis (AD) is a chronic skin condition where nonadherence often results in lack of disease control. Objective We wanted to determine whether the combination of an electronic memory button and a supportive application (app) would affect the Quality of Life and subjective and objective severity measures among AD patients over one month following the patient's normal schedules of treatment. Methods A randomized, investigator-blinded, prospective observational feasibility study for one month where patients diagnosed with AD were randomized based on POEM severity score and divided into 3 groups. The 3 groups were (1) the control group with two consultations, (2) in addition to group 1, patients also received electronic memory buttons to click every time they used their topical products, and (3) in addition to group 2, patients also received an app to track their treatment schedules. At both consultations, patients were evaluated using SCORAD, EASI, POEM, and DLQI. Results 96 patients were enrolled and randomized, of which 83 patients completed the study. EASI and SCORAD scores were lower in all groups at 2nd consultation (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 ( Conclusion A reduction in severity following objective assessments of the AD was observed for all groups and was highly significant for patients offered a memory button and the corresponding app. Furthermore, patients reported a significant subjective beneficial effect if they used the memory button and app. This indicates that digital solutions may have a benefit in clinical practice and may reduce nonadherence and increase the wellbeing of the patients.
The Prognostic Impact of Hormonal Receptor and HER-2 Expression Discordance in Metastatic Breast Cancer Patients

Background Hormone receptor (HR) and human epidermal growth factor receptor (HER2) discordance between primary and metastatic breast cancer lesions is common. However, its impact on long-term survival remains unclear. We aimed to determine the prognostic value of this discordance in patients with metastaticf breast cancer (MBC). Methods A total of 270 patients with MBC who were underwent re-biopsy of progressive metastases at Zhejiang Cancer Hospital from January 1, 2012 to December 31, 2015 with patients consent and then review their primary tumors pathological findings. The HR and HER2 status in both primary and progressive metastatic lesions was determined by immunohistochemistry and/or fluorescence in situ hybridization. The discordance rates were correlated with the clinicopathologic characteristics, metastatic lesions, salvage treatment, and survival analysis in this population. Results A total of 142 (52.6%) MBC patients were diagnosed with discordant HR and HER2 status. Alterations in estrogen receptor (ER), progesterone receptor (PR), and HER2 status were observed in 20.70%, 37.78%, and 11.48% cases, respectively. Chemotherapy (P=0.0192) and endocrine therapy (P=0.048) significantly affected the conversion of HR status. Endocrine therapy was positively correlated with PR discordance (P=0.002), while ER discordance was associated with adjuvant chemotherapy (P=0.031). Survival analysis showed that ER status alterations between primary and metastatic lesions were associated with overall survival (P=0.002). The clinical prognosis was significantly worse with HR losses than with persistent HR positivity (P=0.023). In Cox multivariate analysis, the loss of HR expression and conversion to triple negative were independent prognostic indicators. Conclusion Discordance in HR status between primary and metastatic lesions may impact the prognosis of MBC, and HR conversion has independent prognostic value.
The anatomy, paleobiology, and evolutionary relationships of the largest extinct side-necked turtle

The largest extinct turtle from South America had males with horned shells. Despite being among the largest turtles that ever lived, the biology and systematics of Stupendemys geographicus remain largely unknown because of scant, fragmentary finds. We describe exceptional specimens and new localities of S. geographicus from the Miocene of Venezuela and Colombia. We document the largest shell reported for any extant or extinct turtle, with a carapace length of 2.40 m and estimated mass of 1.145 kg, almost 100 times the size of its closest living relative, the Amazon river turtle Peltocephalus dumerilianus, and twice that of the largest extant turtle, the marine leatherback Dermochelys coriacea. The new specimens greatly increase knowledge of the biology and evolution of this iconic species. Our findings suggest the existence of a single giant turtle species across the northern Neotropics, but with two shell morphotypes, suggestive of sexual dimorphism. Bite marks and punctured bones indicate interactions with large caimans that also inhabited the northern Neotropics.
Decellularized Aortic Scaffold Alleviates H2O2-Induced Inflammation and Apoptosis in CD34+ Progenitor Cells While Driving Neovasculogenesis

Bone marrow-derived stem/progenitor cells have been utilized for cardiac or vascular repair after ischemic injury, but they are subject to apoptosis and immune rejection in the ischemic site. Multiple scaffolds were used as delivery tools to transplant stem/progenitor cells; however, these scaffolds did not show intrinsically antiapoptotic or anti-inflammatory properties. Decellularized aortic scaffolds that facilitate cell delivery and tissue repair were prepared by removing cells of patient-derived aortic tissues. Scanning electron microscopy (SEM) showed cells attached well to the scaffold after culturing for 5 days. Live/dead staining showed most seeded cells survived at day 7 on a decellularized aortic scaffold. Ki67 staining demonstrated that decellularized aortic scaffold promoted proliferation of bone marrow-derived CD34+ progenitor cells. Apoptosis of CD34+ progenitor cells induced by H2O2 at high concentration was significantly alleviated in the presence of decellularized aortic scaffolds, demonstrating a protective effect against oxidative stress-induced apoptosis. Furthermore, decellularized aortic scaffolds significantly reduced the expression of proinflammatory cytokines (IL-8, GM-CSF, MIP-1β, GRO-α, Entoxin, and GRO) concurrently with an increase in anti-inflammatory cytokines (IL-2 and TGF-β) released from CD34+ progenitor cells when exposed to H2O2 at low concentration. Finally, neovascularization was observed by H&E and immunohistochemical staining 14 days after the decellularized aortic scaffolds were subcutaneously implanted in nude mice. This preclinical study demonstrates that the use of a decellularized aortic scaffold possessing antiapoptotic and anti-inflammatory properties may represent a promising strategy for cardiovascular repair after ischemic injury.
Crystallographic characterization of steel microstructure using neutron diffraction

ABSTRACT Applications of neutron diffraction to microstructure evaluation of steel investigated by a project commissioned by the Innovative Structural Materials Association are summarized. The volume fraction of austenite (γ) for a 1.5Mn-1.5Si-0.2C steel was measured by various techniques including backscatter electron diffraction (EBSD) and X-ray diffraction. It is recommended to measure volume fraction and texture simultaneously using neutron diffraction. The γ reverse transformation was in situ monitored using dilatometry, EBSD, X-ray diffraction and neutron diffraction. The γ reversion kinetics showed excellent agreements between dilatometry and neutron diffraction, whereas the γ formation started at higher temperatures in EBSD and X-ray diffraction measurements. Such discrepancy is attributed to the change in chemical compositions at the specimen surface by heating; Mn and C concentrations were decreased with heating. Phase transformations from γ upon cooling were monitored, which enabled us to elucidate the changes in lattice parameters of ferrite (α) and γ affected by not only thermal contraction but also transformation strains, thermal misfit strains and carbon enrichment in γ in the above hypoeutectoid steel. Pearlitic transformation started after the carbon enrichment reached approximately 0.76 mass% and contributed to diffraction line broadening. Martensitic transformation with or without ausforming at 700°C was monitored for a medium carbon low alloyed steel. Dislocation density after ausforming was determined using the convolutional multiple whole profile fitting method for 10 s time-sliced data. The changes in γ and martensite lattice parameters upon quenching were tracked and new insights on internal stresses and the axial ratio of martensite were obtained. GRAPHIAL ABSTRACT
Common functional pain syndromes

### Key points When a patient presents with pain of no obvious organic origin, they are often labelled as having ‘functional’ pain. The exact diagnosis is derived from the organ system displaying the predominant symptoms e.g. musculoskeletal pain in fibromyalgia (FM) or visceral pain in irritable bowel syndrome (IBS). The worldwide prevalence of all functional pain syndromes (FPS) is 15–20%. World Health Organization (WHO) surveys reveal that ∼10% of primary care patients develop a chronic pain condition within 12 months of initial registration. Of these, at least 50% continue to have symptoms beyond 1 yr. FPS cause enormous economic burden on society with concurrent ramifications for the individual's family in particular and society in general. FM alone has been estimated to cost around £4000 per patient per year. There has been a paradigm shift in the understanding of FPS. The old model of multiple discrete chronic pain conditions is being replaced by a more overarching, although no less complex, state of central sensitivity syndrome (CSS). Evidence is being accrued that FPS represent the phenotypic output of a complex interplay between genetic susceptibility, gene–environment interactions, and environmental triggers. Four common FPS will be reviewed in this article: FM, IBS, temporomandibular dysfunction (TMD), and chronic cardiac chest pain (CCCP). The pathophysiology and management of each will be examined and the case presented for a shared underlying mechanism called CSS. Once this new mechanism is adopted more widely, it will allow for future novel management options to be …
Advanced Ultrasound Application – Impact on Presurgical Risk Stratification of the Thyroid Nodules

Aim Current major guidelines recommend risk stratification of the thyroid nodules, after each diagnostic evaluation, in order to focus attention on potentially risky nodules. The main aim of our study was to evaluate the performance of combined advanced ultrasound techniques in this process, compared with conventional stratification models, in order to reduce unnecessary fine-needle biopsies, respectively, surgery. Material and Methods We evaluated 261 cases (261 nodules) using conventional ultrasound (2B), real-time Doppler evaluation (4D) respectively, real-time elastography, using a linear multifrequency probe and a linear volumetric probe (Hitachi Prerius Machine, Hitachi Inc, Japan). All the nodules were classified using a risk stratification model comprising seven conventional US characteristics, two 4 D characteristics and a color map RTE aspect. The results were compared with the pathology results, considered the golden standard diagnosis. Results The prevalence of malignant nodules was 21.83% (57 cases). Conventional risk classification generated: 106 low-risk cases, 113 intermediate-risk and 42 high-risk cases. Our proposed risk classification changes the conventional risk classification with a risk upgrade in 27 cases and with a risk downgrade in 69 cases. The diagnostic quality of the combined risk stratification model was better, considering a low-risk category predictive for benignancy and a high category predictive for malignancy: Sensitivity: 80.88% versus 49.01%, respectively, Specificity: 91.22% versus 54.38. The diagnostic power differences were observed regardless of the nodule size. Conclusion Advanced ultrasound techniques did add diagnostic value in the presurgical risk assessment of the thyroid nodules.