Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting stromal cell Syndecan‐2 reduces breast tumour growth, metastasis and limits immune evasion

Tumour stromal cells support tumourigenesis. We report that Syndecan‐2 (SDC2) is expressed on a nonepithelial, nonhaematopoietic, nonendothelial stromal cell population within breast cancer tissue. In vitro, syndecan‐2 modulated TGFβ signalling (SMAD7, PAI‐1), migration and immunosuppression of patient‐derived tumour‐associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model, overexpression of syndecan‐2 in TASCs significantly enhanced TGFβ signalling (SMAD7, PAI‐1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFβ signalling (SMAD7, PAI‐1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan‐2‐peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFβ‐regulated immunosuppressive genes, such as CXCR4 and PD‐L1. Moreover, using an orthotopic syngeneic breast cancer model, overexpression of syndecan‐2‐peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan‐2 within the TME inhibits tumour growth and metastasis due to decreased TGFβ signalling and increased immune control.
Prolonged Effect of Seminal Plasma on Global Gene Expression in Porcine Endometrium

Seminal plasma (SP) deposited in the porcine uterine tract at the time of mating is known to elicit an initial response that is beneficial for pregnancy outcome. However, whether SP has any long-term effect on alterations in endometrial molecular and cellular processes is not known. In this study, using microarray analyses, differential changes in endometrial transcriptome were evaluated after Day 6 of SP-infusion (6DPI) or Day 6 of pregnancy as compared to corresponding day of estrous cycle. Both, pregnancy and SP induced significant changes in the endometrial transcriptome and most of these changes were specific for a particular group. Functional analysis of differentially expressed genes (DEGs) using Ingenuity Pathway Analysis revealed that inhibition in immune response was affected by both pregnancy and SP infusion. Long-term effects of SP included differential expression of genes involved in inhibition of apoptosis, production of reactive oxygen species and steroid biosynthesis, and activation of processes such as proliferation of connective tissue cells and microvascular endothelial cells. Moreover, interleukin-2 and interferon-γ was identified to be responsible for regulating expression of many DEGs identified on 6DPI. The present study provides evidence for the long-term effects of SP on porcine endometrium that can be beneficial for pregnancy success.
Current status of proton pump inhibitor use in Japanese elderly patients with non-valvular atrial fibrillation: A subanalysis of the ANAFIE Registry

The real-world status of proton pump inhibitor (PPI) use in patients with atrial fibrillation (AF) receiving antithrombotic treatment is largely unknown. The All Nippon AF In the Elderly (ANAFIE) Registry, a prospective, multicenter, observational study, aimed to determine treatment patterns, risk factors, and outcomes among elderly (aged ≥75 years) Japanese non-valvular AF (NVAF) patients in the real-world clinical setting. The present subanalysis of the ANAFIE Registry determined the PPI prescription status of 32,490 elderly Japanese NVAF patients. Patients were stratified by PPI use (PPI+) or no PPI use (PPI−). Risk scores for stroke (CHADS2, CHA2DS2-VASc) and bleeding (HAS-BLED), anticoagulant use, time in therapeutic range (TTR) for warfarin, and anticoagulant/antiplatelet combination use were evaluated. PPIs were used in 11,981 (36.9%) patients. Compared with the PPI− group, the PPI+ group included a greater proportion of female patients (45.2% vs 41.3%; P <0.0001) and had significantly higher CHADS2, CHA2DS2-VASc, and HAS-BLED scores (P <0.0001 for each) as well as higher prevalences of several comorbidities. In the PPI+ group, 54.6% of patients did not have gastrointestinal (GI) disorders and were likely prescribed a PPI to prevent GI bleeding events. Most of the patients with a GI disorder in the PPI+ group had reflux esophagitis. Compared with patients not receiving anticoagulants, a significantly higher proportion of patients receiving anticoagulants received PPIs. For patients receiving anticoagulants, antiplatelet drugs, and both drugs, rates of PPI use were 34.1%, 44.1%, and 53.5%, respectively (P <0.01). Although the rate of PPI use was the highest for NVAF patients receiving both antiplatelet and anticoagulants, no clear differences were observed in the anticoagulants used. These data suggest that PPIs were actively prescribed in high-risk cases and may have been used to prevent GI bleeding among elderly NVAF patients receiving antithrombotic drugs. Trial registration: UMIN000024006
Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6–7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L’Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6–7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6–7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6–7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6–7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.
Association of Education and Depressive Symptoms with Tooth Loss

Previous evidence suggests the association of lower educational attainment and depressive symptoms with tooth loss. The hypothesis of this study was that these factors may exacerbate the effect on tooth loss beyond the sum of their individual effects. We aimed to clarify the independent and interactive effects of educational attainment and depressive symptoms on the number of missing teeth among community residents. Cross-sectional data of 9,647 individuals were collected from the general Japanese population. Dental examination was conducted by dentists. Educational attainment was categorized into 3 levels based on the number of educational years: ≤9, >9 to ≤12, and >12 y. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess depressive symptoms; a total score of ≥16 and/or the use of medications for depression indicate the presence of depressive symptoms. In the multivariate analysis with adjustment for conventional risk factors, educational attainment was identified as a determinant of the number of missing teeth (>9 to ≤12 y of education: coefficient = 0.199, 95% confidence interval [CI], 0.135 to 0.263, P < 0.001; ≤9 y of education: coefficient = 0.318, 95% CI, 0.231 to 0.405, P < 0.001: reference, >12 y of education). An analysis that included interaction terms revealed that the relationship between “≤9 y of education” and the number of missing teeth differed depending on the depressive symptoms, indicating a positive interactive association (coefficient for interaction = 0.198; 95% CI, 0.033 to 0.364, P for interaction = 0.019: reference, >12 y of education). Our study suggests the presence of a significant association between educational attainment and tooth loss, as well as a partial interactive association between “≤9 y of education” and “depressive symptoms” in the general Japanese population.
A national study to assess pharmacists’ preparedness against COVID-19 during its rapid rise period in Pakistan

To evaluate the pharmacist’s preparedness against the COVID-19 during its rapid rise period in Pakistan, an online cross-sectional study was carried out from March 30 to May 22, 2020 among the pharmacists using a pre-validated self-administered questionnaire. A total of 1149 participants completed the survey, amongst which 430(37.9%) were working as retail pharmacists, 216 (18.8%) as community pharmacists, and 213(18.5%) as hospital pharmacists. The mean COVID-19 knowledge score of the participants was 6.77±0.5, which indicated that 84% of them had good knowledge about COVID-19. The multiple linear regression model revealed that attitude was significantly associated with gender (p = 0.001), marital status (p<0.0001) and resident (p = 0.013). The mean practice score was 2.85±0.4, showing that 94% of the participants were following adequate preventive practices against this infection. The results from this study suggest that Pharmacists demonstrated good knowledge, positive attitudes, and acceptable practices regarding COVID-19.
Novel Evidence Concerning Lacrimal Sac Movement Using Ultra-High-Frequency Ultrasound Examinations of Lacrimal Drainage Systems

Purpose: Current hypothesis regarding the mechanism of active tear drainage is based on studies performed ex vivo or under nonphysiological conditions. Novel ultra-high-frequency ultrasound has the advantage of generating images with superior resolution, enabling measurements of low flow in small vessels, and the tracking of tissue motion in real time. The purpose of this study was to investigate the lacrimal drainage system and active drainage using this modality. Methods: The upper lacrimal drainage system was investigated with 40–70 MHz ultrasound in 22 eyes in 13 patients. Irrigation confirmed a lacrimal obstruction in 10 eyes. Motion tracking was used to map movement of the lateral lacrimal sac wall and to measure flow when possible. Results: The anatomy of the upper lacrimal drainage system was mapped in vivo, including the proximal canaliculi, which have not previously been imaged. The lacrimal sac lumen is slit shaped in its resting state but is distended when irrigated or if a nasolacrimal duct obstruction is present. Thus, the healthy lacrimal sac is not a cavity, and the medial retinaculum does not act against a stretched structure. Motion tracking visualized the “lacrimal pump,” showing that the direction of motion of the lateral lacrimal sac wall is mainly in the sagittal plane during blinking. Conclusions: Ultra-high-frequency ultrasound allows detailed physiological monitoring of the upper lacrimal drainage system in vivo. Our findings suggest that current theories of active tear drainage need to be reappraised. Using ultra-high-frequency ultrasound, the greatest direction of motion in the lateral lacrimal sac wall was shown to be in the anterior–posterior direction. This suggests that current active tear drainage theories need to be adjusted. Supplemental Digital Content is available in the text.
Estimand framework: Are we asking the right questions? A case study in the solid tumor setting

The estimand framework requires a precise definition of the clinical question of interest (the estimand) as different ways of accounting for “intercurrent” events post randomization may result in different scientific questions. The initiation of subsequent therapy is common in oncology clinical trials and is considered an intercurrent event if the start of such therapy occurs prior to a recurrence or progression event. Three possible ways to account for this intercurrent event in the analysis are to censor at initiation, consider recurrence or progression events (including death) that occur before and after the initiation of subsequent therapy, or consider the start of subsequent therapy as an event in and of itself. The new estimand framework clarifies that these analyses address different questions (“does the drug delay recurrence if no patient had received subsequent therapy? ” vs “does the drug delay recurrence with or without subsequent therapy? ” vs “does the drug delay recurrence or start of subsequent therapy? ”). The framework facilitates discussions during clinical trial planning and design to ensure alignment between the key question of interest, the analysis, and interpretation. This article is a result of a cross‐industry collaboration to connect the International Council for Harmonisation E9 addendum concepts to applications. Data from previously reported randomized phase 3 studies in the renal cell carcinoma setting are used to consider common intercurrent events in solid tumor studies, and to illustrate different scientific questions and the consequences of the estimand choice for study design, data collection, analysis, and interpretation.
Acute Disseminated Encephalomyelitis: Current Perspectives

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated central nervous system (CNS) disorder, characterized by polyfocal symptoms, encephalopathy and typical magnetic resonance imaging (MRI) findings, that especially affects young children. Advances in understanding CNS neuroimmune disorders as well as the association of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) with both monophasic and recurrent forms of ADEM have led to new insights into its definition, management and outcome. In this review, we aim to provide an update based on current epidemiologic, clinical, radiological and immunopathological aspects and clinical outcome of ADEM.
Co-Ingestion of Black Carrot and Strawberry. Effects on Anthocyanin Stability, Bioaccessibility and Uptake

Although the fate of anthocyanins along digestion has been a matter of research over the last decade, their bioaccessibility so far has been mainly assessed for single administered fruits or vegetables, which is far from the real scenario where they are co-ingested in a meal. Accordingly, the aim of this study was to evaluate the effect of simultaneous intake of fruit and vegetable on in vitro stability, bioaccessibility and uptake of anthocyanins. Black carrot and strawberry were used as food sources of anthocyanins. Anthocyanin identification and quantification were performed using HPLC-Qtof/HPLC-UV. Single matrices and mixtures thereof, were submitted to a standardized in vitro digestion procedure. Anthocyanin uptake was evaluated through an intestinal Caco-2 cell model. Our results showed an increased intestinal stability for specific anthocyanins as a consequence of co-digestion. The presence of the strawberry food matrix positively affected the bioaccessibility of the carrot associated cyanidin-based anthocyanins, whereas no reciprocal effect was observed for pelargonidin-based derivatives in the presence of the black carrot food matrix. Anthocyanin transport was maintained after co-administration. Overall, co-ingestion of black carrot and strawberry did not negatively affect the stability, bioaccessibility or uptake of cyanidin-based anthocyanins, although the effect on pelargonidin-based anthocyanins depended on the type of pelargonidin derivative.
"Zygoma Fractures Are Associated With Increased Morbidity and Mortality in the Pediatric Population".

BACKGROUND Trauma involving the facial bones has been shown to be associated with high severity in previous studies. Characteristics of facial fractures in adults have been well described in the adult population, less so in the pediatric literature. Our investigation aims to define these epidemiological measures and risk factors for poor outcomes using the most recent data. METHODS The 2016 Trauma Quality Improvement Program data bank was examined to study facial fracture pattern, mechanism of injury, and demographic descriptive data to characterize pediatric trauma patients. Multivariable regression analysis was performed to assess risk factors for morbidity and mortality in pediatric facial fracture patients. RESULTS Of 51,168 total pediatric trauma patients, 2917 (5.7%) presented with facial fractures. Motor vehicle trauma was the most common mechanism of injury. Maxillary/malar fractures was the most common fracture type overall. Mandibular fractures were most common in the 0 to 1 age category while nasal bone fractures were more common in older patients. Patients with mandible fractures experienced the highest rate of operative management. Zygoma fracture was highly associated with concomitant traumatic brain injury. Multivariable regression analysis showed that fracture of the zygoma, concomitant traumatic brain injury, and cervical spine injury were risk factors for increased mortality. CONCLUSION Facial fractures are a rare but significant form of trauma in the pediatric population. Our data suggests a slight change in fracture patterns compared to previous studies. Zygoma fractures, traumatic brain injury, and cervical spine injury are risk factors of increased mortality that clinicians should be aware of.
Were domestic camelids present on the prehispanic South American agricultural frontier? An ancient DNA study

The southern boundary of prehispanic farming in South America occurs in central Mendoza Province, Argentina at approximately 34 degrees south latitude. Archaeological evidence of farming includes the recovery of macrobotanical remains of cultigens and isotopic chemistry of human bone. Since the 1990s, archaeologists have also hypothesized that the llama (Lama glama), a domesticated South American camelid, was also herded near the southern boundary of prehispanic farming. The remains of a wild congeneric camelid, the guanaco (Lama guanicoe), however, are common in archaeological sites throughout Mendoza Province. It is difficult to distinguish bones of the domestic llama from wild guanaco in terms of osteological morphology, and therefore, claims that llama were in geographic areas where guanaco were also present based on osteometric analysis alone remain equivocal. A recent study, for example, claimed that twenty-five percent of the camelid remains from the high elevation Andes site of Laguna del Diamante S4 were identified based on osteometric evidence as domestic llama, but guanaco are also a likely candidate since the two species overlap in size. We test the hypothesis that domesticated camelids occurred in prehispanic, southern Mendoza through analysis of ancient DNA. We generated whole mitochondrial genome datasets from 41 samples from southern Mendoza late Holocene archaeological sites, located between 450 and 3400 meters above sea level (masl). All camelid samples from those sites were identified as guanaco; thus, we have no evidence to support the hypothesis that the domestic llama occurred in prehispanic southern Mendoza.
Hospital-Level Variation in the Frequency of Cesarean Delivery Among Nulliparous Women Who Undergo Labor Induction.

OBJECTIVE To evaluate the use of administrative data for identification of labor induction and to estimate the variation in cesarean delivery rates among low-risk women who underwent labor induction. METHODS A cross-sectional study was performed examining live births in California hospitals during 2016 and 2017 using birth certificate data linked with maternal patient discharge records. Initially, eight hospitals performed medical record reviews by using reVITALize definitions on 46,916 deliveries to assess the validity of induction identification by birth certificate or discharge diagnosis records or both. Hospital-level variation in cesarean delivery rates was then assessed among all California hospitals for women with low-obstetric-risk first births before and after further risk adjustment and after the exclusion of potential medical and obstetric indications for induction. Variation in physician-level cesarean delivery rates after induction at four large hospitals also was examined. The relationships between cesarean delivery rates among women with induced labors compared with noninduced labors and with the hospital rate of induction also were explored. RESULTS Identifying induction by a combination of discharge diagnosis codes and birth certificate data had the highest accuracy (92.9%, 95% CI 92.7-93.2). Among 917,225 births at 238 birthing hospitals, there were 99,441 nulliparous women with term, singleton, vertex pregnancies who were induced. The median cesarean delivery rate after labor induction for nulliparous women with term, singleton, vertex pregnancies was 32.2%, with a range of 18.5-84.6%. This wide variation was not reduced after risk adjustment or after exclusion of all women with induction indications. A similar wide variation was noted within geographic regions, neonatal intensive care levels, and among individual physicians in the same facility. Only very weak associations were found for the cesarean delivery rate after labor induction and either the rate after noninduced labor (R<0.08) or the rate of nulliparous labor induction (R<0.12). CONCLUSION The large variation of cesarean delivery rates after induction of labor suggests that clinical management plays an important role in achieving induction success.
Can Magnetic Resonance Radiomics Analysis Discriminate Parotid Gland Tumors? A Pilot Study

Our purpose is to evaluate the performance of magnetic resonance (MR) radiomics analysis for differentiating between malignant and benign parotid neoplasms and, among the latter, between pleomorphic adenomas and Warthin tumors. We retrospectively evaluated 75 T2-weighted images of parotid gland lesions, of which 61 were benign tumors (32 pleomorphic adenomas, 23 Warthin tumors and 6 oncocytomas) and 14 were malignant tumors. A receiver operating characteristics (ROC) curve analysis was performed to find the threshold values for the most discriminative features and determine their sensitivity, specificity and area under the ROC curve (AUROC). The most discriminative features were used to train a support vector machine classifier. The best classification performance was obtained by comparing a pleomorphic adenoma with a Warthin tumor (yielding sensitivity, specificity and a diagnostic accuracy as high as 0.8695, 0.9062 and 0.8909, respectively) and a pleomorphic adenoma with malignant tumors (sensitivity, specificity and a diagnostic accuracy of 0.6666, 0.8709 and 0.8043, respectively). Radiomics analysis of parotid tumors on conventional T2-weighted MR images allows the discrimination of pleomorphic adenomas from Warthin tumors and malignant tumors with a high sensitivity, specificity and diagnostic accuracy.