Purpose Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma. Methods We conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS). Results Between 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare. Conclusion Risk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier NCT01092182).Objectives Specialist palliative care was introduced into the German health care system for patients at the end of life. The primary objective of this study was to assess whether the provision of specialist home palliative care (SHPC) for outpatients increased the likelihood of patients dying at home. Methods We studied data collected in 2015 from a German statutory health insurance company covering 3.872 million people. We evaluated how many patients were identified as needing palliative care and whether these patients were able to stay at home until death. The data were ascertained from general practices in Baden-Wuerttemberg, a part of Germany. Palliative care patients were identified using the International Classification of Diseases (ICD)-10 code Z51.5 or the assigned medical billing code of the German fee schedule. Patients receiving care from an SHPC team were identified using the billing codes 01425 or 01426. Adjusted odds ratios were calculated for the place of death with multivariable logistic regression. Results We found 21,190 (0.55%) palliative patients in the whole population. Of these, 19,507 (92.05%) patients received general palliative care and 1683 (7.95%) patients received specialist palliative care. Mortality rate across all patients was 1.08% (41,800) and mortality rate of palliative patients was 44.08% (9494). In total, 19,833 (47.5%) of the general population died in hospitals, as opposed to only 2208 (23.2%) among palliative patients. Further analysis revealed that of those palliative patients receiving SHPC, 160 (13.3%) died in hospitals as opposed to 2048 (24.7%) of those receiving general care. The probability of dying at home increases already with the label „palliative patient” and gets stronger if care is provided by a specialist palliative care team. Conclusion Most palliative patients are able to die at home. Palliative care teams are responsible for a small part of these patients. Despite the high symptom burden in this group, most are able to die at home.Background In neonatal respiratory distress syndrome, breathing support and surfactant therapy are commonly used to enable the alveoli to expand. Surfactants are typically delivered through liquid instillation. However, liquid instillation does not specifically target the small airways. We have developed an excipient enhanced growth (EEG) powder aerosol formulation using Survanta®. Methods EEG Survanta powder aerosol was delivered using a novel dry powder inhaler via tracheal insufflation to surfactant depleted rats at nominal doses of 3, 5, 10, and 20 mg of powder containing 0.61, 0.97, 1.73, and 3.46 mg of phospholipids (PL), whereas liquid Survanta was delivered via syringe instillation at doses of 2 and 4 mL/kg containing 18.6 and 34 mg of PL. Ventilation mechanics were measured before and after depletion, and after treatment. We hypothesized that EEG Survanta powder aerosol would improve lung mechanics compared with instilled liquid Survanta in surfactant depleted rats. Results and Conclusion EEG Survanta powder aerosol at a dose of 0.61 mg PL significantly improved lung compliance and elastance compared with the liquid Survanta at a dose of 18.6 mg, which represents improved primary efficacy of the aerosol at a 30-fold lower dose of PL. There was no significant difference in white blood cell count of the lavage from the EEG Survanta group compared with liquid Survanta. These results provide an in vivo proof-of-concept for EEG Survanta powder aerosol as a promising method of surfactant replacement therapy.The COVID-19 pandemic has placed front-line health care professionals—who were already at higher risk for negative effects of chronic stress before the pandemic—at even greater risk for depression and anxiety. This article reminds us of the importance of mutual support and caring for our own mental health, including seeking help from our mental health colleagues when needed.Purpose Tumor-infiltrating lymphocytes (TILs) and their spatial characterizations on whole-slide images (WSIs) of histopathology sections have become crucial in diagnosis, prognosis, and treatment response prediction for different cancers. However, fully automatic assessment of TILs on WSIs currently remains a great challenge because of the heterogeneity and large size of WSIs. We present an automatic pipeline based on a cascade-training U-net to generate high-resolution TIL maps on WSIs. Methods We present global cell-level TIL maps and 43 quantitative TIL spatial image features for 1,000 WSIs of The Cancer Genome Atlas patients with breast cancer. For more specific analysis, all the patients were divided into three subtypes, namely, estrogen receptor (ER)-positive, ER-negative, and triple-negative groups. The associations between TIL scores and gene expression and somatic mutation were examined separately in three breast cancer subtypes. Both univariate and multivariate survival analyses were performed on 43 TIL image features to examine the prognostic value of TIL spatial patterns in different breast cancer subtypes. Results The TIL score was in strong association with immune response pathway and genes (eg, programmed death-1 and CLTA4). Different breast cancer subtypes showed TIL score in association with mutations from different genes suggesting that different genetic alterations may lead to similar phenotypes. Spatial TIL features that represent density and distribution of TIL clusters were important indicators of the patient outcomes. Conclusion Our pipeline can facilitate computational pathology-based discovery in cancer immunology and research on immunotherapy. Our analysis results are available for the research community to generate new hypotheses and insights on breast cancer immunology and development.Purpose Institutional efforts toward the democratization of cloud-scale data and analysis methods for cancer genomics are proceeding rapidly. As part of this effort, we bridge two major bioinformatic initiatives the Global Alliance for Genomics and Health (GA4GH) and Bioconductor. Methods We describe in detail a use case in pancancer transcriptomics conducted by blending implementations of the GA4GH Workflow Execution Services and Tool Registry Service concepts with the Bioconductor curatedTCGAData and BiocOncoTK packages. Results We carried out the analysis with a formally archived workflow and container at dockstore.org and a workspace and notebook at app.terra.bio. The analysis identified relationships between microsatellite instability and biomarkers of immune dysregulation at a finer level of granularity than previously reported. Our use of standard approaches to containerization and workflow programming allows this analysis to be replicated and extended. Conclusion Experimental use of dockstore.org and app.terra.bio in concert with Bioconductor enabled novel statistical analysis of large genomic projects without the need for local supercomputing resources but involved challenges related to container design, script archiving, and unit testing. Best practices and cost/benefit metrics for the management and analysis of globally federated genomic data and annotation are evolving. The creation and execution of use cases like the one reported here will be helpful in the development and comparison of approaches to federated data/analysis systems in cancer genomics.Recent advances in the understanding of underlying molecular signaling mechanisms of cancer susceptibility and progression have led to an increase in the use of targeted therapies for cancer treatment. Despite improvements in survival with new treatment options in oncology, resistance to therapy is a major obstacle to the long-term effectiveness of targeted agents in metastatic cancer treatment, culminating in insensitivity to treatment and tumor outgrowth. Adaptive resistance can play an important role in primary and upfront resistance to therapy as well as in secondary or acquired resistance. By focusing on colorectal and breast tumors, we discuss how therapeutic combinations based on specific drivers of tumor biology can be used to overcome resistance. We present how monitoring tumor dynamics over time may allow early adaptation of treatment. Breast cancer is the most common malignancy in women worldwide, and the majority of these cancers are sensitive to endocrine therapy (ET) blocking the production of or response to estrogen. However, primary and acquired resistance limits efficacy. Recent combinations of agents targeted to pathways that drive tumor growth resistance with ET have resulted in remarkable improvements in disease response and control, improving survival in some settings. In this review, we summarize adaptive resistance mechanisms, approaches to combination strategies, and dynamic tumor monitoring to improve efficacy and overcome resistance. We provide examples of combination therapy to enhance the efficacy of targeted therapies in breast and colorectal tumors.Changes in the health insurance coverage landscape in the United States during the past decade have important implications for receipt and affordability of cancer care. In this paper, we summarize evidence for the association between health insurance coverage and cancer prevention and treatment. We then discuss ongoing changes in health care coverage, including implementation of provisions of the Affordable Care Act, increasing prevalence of high-deductible health insurance plans, and factors that affect health care delivery, with a focus on vertical integration of hospitals and providers. We summarize the evidence for the effects of the changes in health coverage on care and discuss areas for future research with the goal of informing efforts to improve cancer care delivery and outcomes in the United States.The rapid expansion of modern cancer immunotherapeutics has led to a dramatic improvement in patient survival and sustained remission for otherwise refractory malignancies. However, a significant limitation behind these current treatment modalities is an irregularity in clinical response, which is especially pronounced among checkpoint inhibition. This unpredictability leads to significant side effects, financial costs, and health care burden, with unsatisfactory clinical benefit in the majority of treated patients. Additionally, although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit. This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting. Herein, we discuss current advantages of predictive biomarkers, as well as limitations in their clinical use and application. We also review future directions, ideal characteristics, and trial design needed for proper precision immuno-oncology and biomarker development.Background Graft bridging is used in massive rotator cuff tear (MRCT); however, the integration of graft-tendon and graft-bone is still a challenge. Hypothesis A co-electrospinning nanoscaffold of polycaprolactone (PCL) with an „enthesis-mimicking” (EM) structure could bridge MRCT, facilitate tendon regeneration, and improve graft-bone healing. Study design Controlled laboratory study. Methods First, we analyzed the cytocompatibility of the electrospinning nanoscaffolds, including aligned PCL (aPCL), nonaligned PCL (nPCL), aPCL-collagen I, nPCL-collagen II, and nPCL-nanohydroxyapatite (nHA). Second, for the EM condition, nPCL-collagen II and nPCL-nHA were electrospun layer by layer at one end of the aPCL-collagen I; for the control condition, the nPCL was electrospun on the aPCL. In 40 mature male rats, resection of both the supraspinatus and infraspinatus tendons was performed to create MRCT, and the animals were divided randomly into EM and control groups. In both groups, one end of the layered structure wantrol group at 8 weeks. Conclusion The co-electrospinning nanoscaffold of aPCL-collagen I could be used as a bridging graft to improve early graft-tendon healing for MRCT in a rat model and enhance early enthesis reconstruction in combination with a multilayered structure of nPCL-collagen II and nPCL-nHA. Clinical relevance We constructed a graft to bridge MRCT, enhance graft-tendon healing and graft-bone healing, and reconstruct the enthesis structure.Objective To define critical elements that contribute to successful parathyroidectomy based on a high-volume single-surgeon experience and explore learning curve characteristics. Study design Systematic analysis of prospectively maintained quality assurance database. Setting Academic tertiary care endocrine surgery practice. Subjects and methods In total, 4737 consecutive patients who underwent thyroid or parathyroid surgery from 2004 to 2020 were identified. Demographic data acquisition was undertaken on a subset of these patients who had initial surgery for primary hyperparathyroidism during the academic years 2005 to 2018. Patients with renal or syndromic hyperparathyroidism and those undergoing reoperative surgery were excluded. Results From 1710 patients who underwent parathyroid surgery, 1082 met inclusion criteria in order to focus on a homogeneous data set. These patients had a mean age of 60.1 ± 12.5 years and 76.4% were female. The overall cure rate was 98.3%, reflecting a success rate that increased from 95.5% during the first 200 cases to 99.7% over the final 300 cases. The complication rate was 1.7%. Over 2 decades, the patient phenotype evolved toward milder disease and smaller adenomas. A learning curve of 200 cases was required to become a proficient parathyroid surgeon; to achieve exceptional results required several hundred additional cases. Parathyroid surgery represents a higher proportion of an endocrine surgery practice than previously (54.0% in 2019 compared with 25.5% in 2004). Conclusion A focused practice dedicated to endocrine surgery yields surgical volumes exceeding 500 cases annually. There has been a steady shift toward parathyroid surgery. A lengthy learning curve can be shortened by pursuit of several specific strategies that are outlined in detail.Objective As awareness of educator stress and burnout is at the forefront of issues faced in the education system, programs are being implemented to focus on the well-being and betterment of educators. Mindfulness is one such practice that has been found to increase wellness and, in many cases, decrease negative outcomes. In this study, the effects of a Mindfulness-Based Stress Reduction Program were measured in grade-school (K-12) educators. Design A longitudinal noncontrolled trial of educators who completed baseline and short- and long-term postintervention surveys. Location Miami-Dade County. Subjects Two hundred thirty-six educators who worked in K-12 public and private schools. Intervention An 8-week Mindfulness-Based Stress Reduction Program. Outcome measures Five Facet Mindfulness Questionnaire, Self-Compassion Scale, Maslach Burnout Inventory-Educators, Patient-Reported Outcome Measurement Information System (PROMIS-29) for measuring physical and mental health functionality. Results The multiple linear regression analysis of the short-term cohort data yielded statistically significant improvements in mindfulness, self-compassion, and personal accomplishment and decreases in isolation, anxiety, fatigue, and emotional exhaustion. In the long-term cohort, repeated measures regression showed self-compassion and mindfulness continued to improve significantly, whereas negative outcomes of fatigue and sleep disturbance showed statistically significant decreases. Effect sizes were calculated for all the measures, many of which were medium sized, total mindfulness (0.69), self-compassion (0.051), and sleep disturbance (0.49). Conclusion Findings are consistent with previous literature and support the need for such programs that impact the educator’s personal and professional experience.Many bacteria and archaea possess an RNA-guided adaptive and inheritable immune system that consists of clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins. In most CRISPR-Cas systems, the maturation of CRISPR-derived small RNAs (crRNAs) is essential for functionality. Cas6 endonucleases function as the most frequent CRISPR RNA maturation enzymes. In the cyanobacterium Anabaena sp. PCC 7120, ten CRISPR loci are present, but only two cas gene cassettes plus a Tn7-associated eleventh array. In this study, we deleted the two cas6 genes alr1482 (Type III-D) or alr1566 (Type I-D) and tested the specificities of the two corresponding enzymes in the resulting mutant strains, as recombinant proteins and in a cell-free transcription-translation system. The results assign the direct repeats (DRs) to three different groups. While Alr1566 is specific for one group, Alr1482 has a higher preference for the DRs of the second group but can also cleave those of the first group. We found that this cross-recognition limits crRNA accumulation for the Type I-D system in vivo. We also show that the DR of the cas gene-free CRISPR array of cyanophage N-1 is processed by these enzymes, suggesting that it is fully competent in association with host-encoded Cas proteins. The data support the functionality of CRISPR arrays that frequently appear fragmented to multiple genomic loci in multicellular cyanobacteria and disfavor other possibilities, such as the nonfunctionality of these orphan repeat-spacer arrays. Our results show the functional coordination of Cas6 endonucleases with both neighboring and remote repeat-spacer arrays in the CRISPR-Cas system of cyanobacteria.Biological psychiatry scholarship on posttraumatic stress disorder (PTSD) is making strides with new omics technologies. In this context, there is growing recognition that noncoding RNAs are vital for the regulation of gene and protein expression. Long noncoding RNAs (lncRNAs) can modulate splicing, influence RNA editing, messenger RNA (mRNA) stability, translation activation, and microRNA-mRNA interactions, are highly abundant in the brain, and have been implicated in neurodevelopmental disorders. The largest subclass of lncRNAs is long intergenic noncoding RNAs (lincRNAs). We report on lincRNAs and their predicted mRNA targets associated with fear extinction induced by co-administration of D-cycloserine and behavioral fear extinction in a PTSD animal model. Forty-three differentially expressed lincRNAs and 190 differentially expressed mRNAs were found to be associated with fear extinction. Eight lincRNAs were predicted to interact with and regulate 108 of these mRNAs, while seven lincRNAs were predicted to interact with 22 of their pre-mRNA transcripts. Based on the functions of their target mRNAs, we inferred that these lincRNAs bind to nucleotides, ribonucleotides, and proteins; subsequently influence nervous system development, morphology, and immune system functioning; and could be associated with nervous system and mental health disorders. We found the quantitative trait loci that overlapped with fear extinction-related lincRNAs included traits such as serum corticosterone level, neuroinflammation, anxiety, stress, and despair-related responses. To the best of our knowledge, this is the first study to identify lincRNAs and their RNA targets with a putative role in transcriptional regulation during fear extinction in the context of an animal model of PTSD.Cumulative cultural learning has been argued to rely on high-fidelity copying of other individuals’ actions. Iconic gestures of actions have no physical effect on objects in the world but merely represent actions that would have an effect. Learning from iconic gestures thus requires paying close attention to the teacher’s precise bodily movements-a prerequisite for high-fidelity copying. In three studies, we investigated whether 2- and 3-year-old children (N = 122) and great apes (N = 36) learn novel skills from iconic gestures. When faced with a novel apparatus, participants watched an experimenter perform either an iconic gesture depicting the action necessary to open the apparatus or a gesture depicting a different action. Children, but not great apes, profited from iconic gestures, with older children doing so to a larger extent. These results suggest that high-fidelity copying abilities are firmly in place in humans by at least 3 years of age.It is widely assumed that people will share inaccurate gossip for their own selfish purposes. This assumption, if true, presents a challenge to the growing body of work positing that gossip is a ready source of accurate reputational information and therefore is welfare improving. We tested this inaccuracy assumption by examining the frequency and form of spontaneous lies shared between gossiping members of networks playing a series of one-shot trust games (N = 320). We manipulated whether gossipers were or were not competing with each other. We showed that lies make up a sizeable minority of messages and are twice as frequent under gossiper competition. However, this had no discernible effect on trust levels. We attribute this to the findings that (a) gossip targets are insensitive to lies and (b) some lies are welfare enhancing. These findings suggest that lies need not prevent-and may help-gossip to serve reputational functions.This study employed a multi-dimensional (i.e., orthographic, phonological, and semantic) and bi-level (i.e., character and radical) approach to analyze the character writing of 120 Hong Kong Chinese children with developmental dyslexia in Grades 2-5 and 120 typically developing age-matched controls. Relative to their typically developing peers, children with dyslexia were less sensitive to the positional and functional consistencies of sublexical radicals and exhibited prolonged use of phonology at the character level as grade-level advanced. Furthermore, the children with dyslexia relatively relied more on phonology at the radical level than younger, reading level-matched children. These results indicate the effects of implicit statistical learning on the development of Chinese character writing skills and suggest that the prolonged use and overreliance on phonology in character writing by Chinese children with dyslexia may reflect their difficulties in implicit statistical learning.Introduction Obesity predisposes patients to the development of abdominal wall hernias. Ventral hernia incidence, size, and recurrence rate are all increased in this population. As such, the surgeon is likely to encounter patients presenting for metabolic and bariatric surgery with existing ventral hernias. Controversy persists regarding the algorithm for treatment in this situation. Do we wait to repair, or is the weight inconsequential? Materials and Methods We critically reviewed the available literature accessed through PubMed on the repair of ventral hernias in the obese population. Specifically, we focused on the outcomes after staged repair versus concurrent repair at the time of bariatric surgery. We aim at providing an overview of the conclusions from past and present publications with commentary by the authors. Results A review of the literature finds conflicting opinions regarding the safety and success of concurrent ventral hernia repair at the time of bariatric surgery. Obese patients frequently have complex hernias and are predisposed to poor wound healing and increased recurrence. Although some small studies find success with concurrent repair, large registry analyses as well as expert consensus statements advocate for staged repair. Conclusion For the obese patient with large ventral hernia, the authors recommend a staged approach, beginning with bariatric surgery and deferring the hernia repair until significant weight loss is obtained. The exception exists, and each patient must be evaluated critically regarding hernia size, contents, and risk of obstruction if left untreated.The human gut microbiota develops soon after birth and can acquire inter-individual variation upon exposure to intrinsic and environmental cues. However, inter-individual variation has not been comprehensively assessed in a multi-ethnic study. We studied a longitudinal birth cohort of 106 infants of three Asian ethnicities (Chinese, Malay, and Indian) that resided in the same geographical location (Singapore). Specific and temporal influences of ethnicity, mode of delivery, breastfeeding status, gestational age, birthweight, gender, and maternal education on the development of the gut microbiota in the first 2 years of life were studied. Mode of delivery, breastfeeding status, and ethnicity were identified as the main factors influencing the compositional development of the gut microbiota. Effects of delivery mode and breastfeeding status lasted until 6M and 3M, respectively, with the primary impact on the diversity and temporal colonization of the genera Bacteroides and Bifidobacterium. The effect of ethnicity was apparent at 3M post-birth, even before the introduction of weaning (complementary) foods, and remained significant after adjusting for delivery mode and breastfeeding status. Ethnic influences remained significant until 12M in the Indian and Chinese infants. The microbiota of Indian infants was characterized by higher abundances of Bifidobacterium and Lactobacillus, while Chinese infants had higher abundances of Bacteroides and Akkermansia. These findings provide a detailed insight into the specific and temporal influences of early life factors and ethnicity in the development of the human gut microbiota. Trial Registration Clinicaltrials.gov registration no. NCT01174875.Numerous studies have been carried out on the bioactive properties of hydroxytyrosol (HT) in olive oils (OOs), although there are few reports comparing anti-inflammatory activity among different olive varieties or regions of production. The purpose of this study was to investigate the in vitro inflammatory action of HT in extracts of four OO varieties in the Languedoc region of the French Mediterranean. Factors other than cultivar were eliminated, which enabled unambiguous varietal differences to be identified. Purified extracts of OO were obtained using an optimized solid-phase extraction procedure by which only polar compounds were recovered. High performance liquid chromatography-photodiode array detection-tandem mass spectrometry was used to identify and quantify HT and oleacein in the extracts. The total polyphenol concentration ranged from 93.00 mg gallic acid equivalent/kg OO for Picholine to 27 mg gallic acid equivalent for Verdale OOs. The concentrations of HT in Picholine, Olivère, and Lucques varier other bioactive compounds in OO. [Figure see text].Genetic information, both germline and somatic, is an increasingly important consideration in therapeutic decision-making in cancer. Germline mutations in genes associated with increased cancer risk can identify those individuals without cancer who may benefit from enhanced screening and prevention strategies. In individuals with cancer, germline and somatic mutations may help to guide local and systemic management decisions. Here, we review considerations of these issues in selected cancer types.Research suggests that toddlers with regulation issues engage in significantly more media use than toddlers without regulation difficulties, and this may be due, in part, to parental strain associated with parenting a child who is difficult to regulate or soothe. The current study sought to determine if the observed relationship between parental strain and child media use in the context of regulation difficulties continues into the preschool years. Data from the 2016 (N = 6,976) and 2017 (N = 3,056) National Survey of Children’s Health were used to test a structural equation model (SEM) examining the moderating effect of parenting strain on the relationship between child media use and child regulation after controlling for socioeconomic status (SES) and adverse childhood experiences. The SEM had reasonable model fit. The study did not find a moderating effect for parenting strain but did identify a small significant relationship between child media use and regulation after controlling for parenting strain and SES. Additionally, SES proved to be a strong moderator of regulation and child media use. These findings point to the possibility that the relationship between parental strain and child media use may be more directly related to perceived ability to calm their child identified in previous research rather than perception of child’s difficulty. This study demonstrated that the negative link between child media use and regulation may persist into the preschool years. Limitations of the study include broad items used to assess time spent with media and limited depth of questions associated with regulation and parenting strain.Total joint arthroplasty is a rapid recovery procedure with patients optimized quickly in preparation for discharge. Two significant postoperative goals are effective pain management and prevention of postoperative venous thromboembolism (VTE). Low-risk patients receive aspirin 81 mg twice daily for VTE prophylaxis; this dosing regimen has been reduced over the past few years from 325 mg to 162 mg to 81 mg twice daily. Unless contraindications exist, all patients receive multimodal pain management that includes the use of celecoxib or meloxicam. Upon reduction of the aspirin dose to 81 mg twice daily, we rapidly identified 2 patients who developed a pulmonary embolus when celecoxib or meloxicam was administered concurrently with aspirin. The interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin varies among the different NSAIDs. It is also highly dependent on numerous factors, including time of administration, dose of aspirin, and both pharmacodynamics and dose of the NSAID. Real-world outcomes of concomitant administration of NSAIDs with low-dose aspirin led to increased incidence of VTE, possibly due to competitive inhibition of aspirin at platelet receptor sites. This interaction was mitigated by altering the administration times of both agents.Objectives The purpose of this study was to compare the accuracy of imaging techniques in diagnosing periapical lesions. Methods Imaging records of 80 patients (51 females, 29 males, aged between 14 and 75 years) including periapical and panoramic radiographs and ultrasonographic images were selected from databases of Selcuk University Dentistry Faculty. Periapical radiographs were accepted as gold-standard and 160 anterior maxillary and mandibular teeth with or without periapical lesion were included to the study. Three specialist observers (dental radiologists) evaluated the presence and appearance of periapical lesions on panoramic radiograph and ultrasonographic images.Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic value of panoramic radiographs and ultrasonography were determined. Results Sensitivity was 0.80 and 0.77 for ultrasonographic images and panoramic radiographs, respectively which shows that periapical lesion was correctly detected in 80% of the cases with ultrasound and in 77% of the cases with panoramic radiography. Specificity values were determined as 0.97 for ultrasound and 0.95 for panoramic radiography. Overall diagnostic accuracy was 0.86 and 0.84 for ultrasound and panoramic radiography, respectively. Conclusions Periapical and panoramic radiographs are commonly used to visualize periapical lesions. Besides, ultrasonography is an alternative method to digital radiographic techniques in the diagnosis of anterior teeth with periapical lesions.Lipoprotein(a) (Lp(a)) was discovered more than 50 years ago, and a decade later, it was recognized as a risk factor for coronary artery disease. However, it has gained importance only in the past 10 years, with emergence of drugs that can effectively decrease its levels. Lp(a) is a low-density lipoprotein (LDL) with an added apolipoprotein(a) attached to the apolipoprotein B component via a disulphide bond. Circulating levels of Lp(a) are mainly genetically determined. Lp(a) has many functions, which include proatherosclerotic, prothrombotic and pro-inflammatory roles. Here, we review recent data on the role of Lp(a) in the atherosclerotic process, and treatment options for patients with cardiovascular diseases. Currently 'Proprotein convertase subtilisin/kexin type 9′ (PCSK9) inhibitors that act through non-specific reduction of Lp(a) are the only drugs that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. The effects of PCSK9 inhibitors are not purely through Lp(a) reduction, but also through LDL cholesterol reduction. Finally, we discuss new drugs on the horizon, and gene-based therapies that affect transcription and translation of apolipoprotein(a) mRNA. Clinical trials in patients with high Lp(a) and low LDL cholesterol might tell us whether Lp(a) lowering per se decreases cardiovascular morbidity and mortality.KEY MESSAGESLipoprotein(a) is an important risk factor in patients with cardiovascular diseases.Lipoprotein(a) has many functions, which include proatherosclerotic, prothrombotic and pro-inflammatory roles.Treatment options to lower lipoprotein(a) levels are currently scarce, but new drugs are on the horizon.This study explored the efficacy and safety of rivaroxaban in elderly patients, at different doses and age of patients, and analyzed risk factors of bleeding. A retrospective analysis was conducted of 299 patients aged 60 years or older who were admitted to the First Hospital of Jilin University between January 2016 and August 2018. It was found that the rate of bleeding events (but not embolism) significantly increased as the dose of oral rivaroxaban increased (P less then .001), and with age, especially in patients aged ≥80 years (P = .001, both). The multivariate logistic regression analysis indicated that age (odds ratio [OR] 2.963, 95% CI 1.627-5.396) and the daily dose of rivaroxaban (OR 2.325, 95% CI 1.483-3.645) were independent risk factors for bleeding. The study determined that rivaroxaban anticoagulant therapy is effective in the elderly patients, but the risk of bleeding increases with age, and is a concern especially in the most old patients. The recommended daily dose of rivaroxaban is effective, but a lower dose is safer for the elderly patients.The use of stable isotopes (δ2H and δ18O) is widespread in water resources studies. In the Latin America and the Caribbean (LAC) region, the application of isotope techniques has increased in the past decade, but there remains room to gain self-reliance in environmental isotope studies, necessitating easy and fast access to good-quality isotope data. To that end, in 2018 the IAEA carried out the first regional interlaboratory comparison exercise, testing the analytical performance of 25 laboratories using isotope-ratio mass spectrometry and laser absorption spectroscopy. The three test samples covered a commonly observed range of 0 to -16 ‰ δ18O and 0 to -115 ‰ δ2H. z- and ζ-scores were used to benchmark laboratories’ performance against a strict criterion. We found that 81% of the laboratories had satisfactory performance ([Formula see text]≤ 2) for δ2H but only 54% achieved similar scores for δ18O. Only a minor fraction of results (12% for δ2H and 15% for δ18O) were unsatisfactory. The larger number of questionable results for δ18O confirmed the challenges in laser absorption spectroscopy for this isotope. Besides instrumental performance, the sample throughput, laboratory reference materials, and data post-processing were contributing factors to inaccurate or imprecise performance.Background Prostate cancer is the most common type of cancer for men in many countries. One of the various prostate cancer therapy methods is hormone therapy, and explaining the association between androgen hormones and prostate cancer is a critical role for successful prostate cancer treatment. Materials and Methods In the current study, the behavior of 3,4- divanillyltetrahydrofuran (DTH) was examined against prostate cancer cells, which have androgen sensitivity differences [LNCaP (+), PC3 (-)]. For this aim, DTH was obtained by extraction of Urtica dioica roots. The molecular structure of isolated compound was confirmed as DTH by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy analyses. To evaluate the association of androgen sensitivity, DTH was radiolabeled with 131I, and cell uptake assay was performed by using 131I-radiolabeled DTH. Also, cytotoxicity (WST-1) assay of DTH was performed against LNCaP and PC3 cells to determinate the toxic effects of DTH on different androgen mechanisms. Results The results of assays on cells have shown that DTH lignan behaves different like being more toxic to LNCaP cells than PC3 cells, depending on androgen sensitivity. Conclusion The results may contribute both the research topics of phytolignan prostate cancer and androgen-sensitive prostate cancer.Background There is a dearth of comparative accuracy studies of continuous glucose monitoring (CGM) devices in the home-use setting, and none with the Eversense implantable CGM. Methods We evaluated the accuracy of the Dexcom G5, Abbott Freestyle Libre Pro, and Senseonics Eversense during a 6-week, free-living, home-use bionic pancreas study involving 23 subjects with type 1 diabetes who wore all 3 devices concurrently. The primary outcome was the mean absolute relative difference (MARD) between CGM readings and point-of-care (POC) plasma-glucose (PG) values obtained approximately twice daily by the subjects. We compared PG values with CGM readings when available from all 3 CGMs in the 5 minutes preceding the PG values (n=829 sets). Since the Libre Pro records readings every 15 minutes, we also did a two-way comparison between the G5 and the Eversense with a higher number of comparisons (n=2277 sets). Results All 3 CGM systems produced higher average MARDs than during in-clinic studies. However, since all three CGM systems were worn by the same individuals and used the same meter for comparator PG measurements, we could directly compare their performances. In the 3-way comparison, Eversense achieved the lowest nominal MARD (14.8%) followed by Dexcom G5 (16.3%) and Libre Pro (18.0%) (Eversense versus Libre Pro p=0.004, other comparisons p=NS). There was a statistically significant difference (p=0.008) in the 2-way comparison of the MARDs for Eversense (15.1%) and G5 (16.9%). Conclusions The point accuracy of the Eversense was better than two other CGMs when compared with POC PG values.The demand for fresh groundwater in the Jaffna peninsula in northern Sri Lanka, has been increasing as the only water source for domestic and agricultural needs. Isotopic and hydro-chemical assessment on groundwater recharge and quality was done with the objective of assisting groundwater management plans. Water samples were collected in pre and post monsoon periods for isotope analyses (2H, 18O and 3H) and major ions. Isotope data provide evidence that the groundwater is predominantly recharged by inter-monsoon (convectional) and North-East monsoon rains. Different residence times of shallow groundwater were found. The study revealed that the groundwater quality is mainly deteriorated due to dissolution of geogenic elements. However, in some instances, seawater intrusion and evaporation have caused lowering of groundwater quality. More saline groundwater is found in deeper levels in the karstic limestone aquifer system. Fresh water is available in coastal sandy aquifers in the eastern part of the peninsula. The impact of rainfall variations and agricultural activities are contributory factors for producing variations in the quality of groundwater. The current study suggests artificial groundwater recharge for the development and utilization of groundwater resources through small scale tanks/reservoirs or ponds in the areas where direct rain recharge occurs.Objectives Multiple reasons for suboptimal treatment of breakthrough cancer pain (BTcP) have been reported in the literature. We aimed to ascertain the perception of physicians on the potential inappropriate use and prescription of rapid-onset opioids (ROOs) for breakthrough cancer pain (BTcP) and the causes thereof.Methods Observational study based on an online survey addressed to doctors from different specialties (radiation oncology, medical oncology, anesthesia, palliative care and general practitioners) with experience in the management of BTcP in the Spanish public health setting.Results A total of 114 eligible specialists mainly from radiation oncology (37.7%), medical oncology (24.6%) and pain units (18.4%) participated in the study. Most agreed on important aspects of BTcP management, such as their preference for ROOs or the need for early follow-up after treatment initiation. However, their answers revealed a lack of standardization of BTcP diagnosis. Half of respondents believed that their BTcP patients might misuse ROOs. Physicians polled believed that lack of training in pain management (71.9%) and inadequate BTcP diagnosis and evaluation (66.7%) were the greatest obstacles for prescribing opioids. Specialists also thought that they do not provide the necessary information to patients (51.8%) and caregivers (57.9%) to guarantee the correct use of these drugs.Conclusions These results are of utmost importance as they highlight the need to increase physicians’ awareness of BTcP and its management and the need to improve communication with patients and their caregivers. Our findings also indicate the need for future research on the possible misuse of opioids in BTcP patients and its causes.Bone marrow-derived mesenchymal stem cells (BMSCs) from livestock are valuable resources for veterinary therapeutics and animal reproduction. Previous studies have shown that hypoxic conditions were beneficial in maintaining the mesenchymal feature of BMSCs. However, the effects of hypoxia on buffalo BMSCs (bBMSCs) remain unclear. In this study, the effects of hypoxic conditions on cell morphology, migration, polarity, and karyotype of bBMSCs were examined. The results showed that hypoxia (5% oxygen) enhanced colony formation and stress fiber synthesis of bBMSCs. Under the hypoxic culture conditions, the migration capacity and normal karyotype rate of bBMSCs were significantly improved (p less then 0.05), which resulted in weakened cell polarity and enhanced karyotype stability in bBMSCs. In addition, it was significantly (p less then 0.05) upregulated in the expression levels of HIF-TWIST signaling pathway axis-related genes (Hif-1, Hif-2, Twist, Snail, Slug, Fn1, N-cadherin, Collal). The HIF-TWIST axis of bBMSCs was also activated in hypoxia. Finally, it was more effective and easier to maintain the mesenchymal feature of bBMSCs in hypoxic conditions. These findings not only provide theoretical guidance to elucidate the detailed regulation mechanism of hypoxia on mesenchymal nature maintenance of bBMSCs, but also provide positive support to further establish the stable in vitro culture system of bBMSCs.Many cancer cells share the property of carrying out markedly elevated rates of glycolysis to generate energy even in the presence of sufficient oxygen, and this is known as the Warburg effect. In recent years, there has been a resurgence of interest in the Warburg effect, as the field of oncology has amassed evidence that cellular metabolism may play a prominent role in many neoplasms. Largely in the past decade, another prominent and perhaps surprising factor has emerged in the cancer literature the catecholamine molecules, epinephrine (adrenaline) and norepinephrine (noradrenaline), appear to play a role in tumorigenesis and metastasis. The drug propranolol, which blocks beta adrenergic receptors, may be therapeutic in human angiosarcoma, melanoma, and ovarian cancer. The current paper synthesizes these older and more recent findings, in an attempt to unify the major factors that contribute to tumorigenesis. This paper suggests that in addition to the direct interaction of catecholamine signaling with genetic risk factors (including mutagenesis), it interacts with environmental factors such as hypertension, obesity, unhealthy dietary components, physical inactivity, substance abuse, and mental or emotional stress, to promote the Warburg effect by facilitating glucose availability through suppression of pancreatic insulin release. Further, it proposes that many cancer cells synthesize and release catecholamines to activate their own receptors in an autocrine fashion. In summary, catecholamines are an important „new” factor in cancer that may interface with both genetics and environmental factors to alter the Warburg effect and modulate tumorigenesis.Nasopharyngeal cancer (NPC) is a type of head and neck cancer with a high rate of metastasis. Circular RNAs (circRNAs) were reported to be related to the development of human cancers. This research aimed to investigate the functional mechanism of circRNA circ_0000615 in NPC. The gene expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to assess cell proliferation ability. Transwell assay was used to measure cell migratory and invasive abilities. Furthermore, the interaction between miR-338-3p and circ_0000615 or fibroblast growth factor 2 (FGF2) was predicted by starBase v.2.0 and then confirmed by the dual-luciferase reporter assay. Besides, the mouse xenograft experiment was carried out to explore the effect of circ_0000615 on tumor growth in vivo. We detected increased levels of circ_0000615 and FGF2, along with the decreased level of miR-338-3p NPC tissues and cells. Circ_0000615 knockdown suppressed the proliferation, migration, invasion, and EMT of NPC cells. Interestingly, circ_0000615 interacted with miR-338-3p, and miR-338-3p targeted FGF2. Circ_0000615 inhibited miR-338-3p expression to upregulate FGF2 level. Furthermore, both miR-338-3p depletion and FGF2 overexpression weakened the effect of circ_0000615 knockdown on NPC cell progression. Besides, circ_0000615 knockdown repressed tumor growth in vivo. In conclusion, our findings demonstrated that circ_0000615 knockdown suppressed the growth of NPC cells via modulating miR-338-3p/FGF2 axis, providing a theoretical basis for the treatment of NPC.Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. In this study, we investigated the role of miR-346 in RCC cells under hypoxia. OS-RC-2 and 786-O cells were cultured in 1% O2 or normal oxygen. Cell proliferation, migration, and invasion abilities were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, transwell migration, and invasion assays, respectively. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-346 and N-myc downstream-regulated gene 2 (NDRG2). Then bioinformatics analysis, dual-luciferase reporter assay, and RNA immunoprecipitation were carried out to determine the relationship between miR-346 and NDRG2. The protein expression of NDRG2 was detected by western blot assay. Hypoxia promoted cell proliferation, migration, and invasion in OS-RC-2 and 786-O cells. Meanwhile, we found that miR-346 was upregulated in RCC cells under hypoxia as relative to normoxia. miR-346 deletion could decrease the viability, migration, and invasion abilities of RCC cells under hypoxia. Besides, our data demonstrated that NDRG2 was a target gene of miR-346. The expression of NDRG2 in OS-RC-2 and 786-O cells was lower under hypoxia than under normal oxygen conditions. Moreover, NDRG2 overexpression could inhibit cell proliferation, migration, and invasion in RCC cells under hypoxia. And NDRG2 silencing reversed the inhibitory effects of the miR-346 inhibitor on the viability, migration, and invasion abilities of RCC cells in hypoxia conditions. miR-346 promoted the viability, migration, and invasion of RCC cells under hypoxia by targeting NDRG2.For patients with clinically early-stage localized prostate cancer, radiotherapy is another treatment that can achieve radical treatment in addition to radical prostatectomy. Despite this, there is still a large number of patients with prostate cancer who have a biochemical recurrence after undergoing radiotherapy, or even clinical recurrence, leading to treatment failure. Although the expression of the fructose-1,6-bisphosphatase-1 (FBP1) gene has been found to be absent in various tumors and is associated with a poor prognosis in tumor patients. However, the expression and role of FBP1 in prostate cancer are not clear. The purpose of this study was to investigate the role and mechanism of FBP1 in the radiotherapy resistance of prostate cancer. By analyzing the microarray data of prostate cancer radiotherapy resistant cells and parental cells (GSE53902), we found that FBP1 expression in DU145 radiotherapy resistant cells was significantly higher than in the DU145 parental cells. In addition, we searched for the expression of FBP1 in 492 prostate cancer samples from TCGA and found that its expression in prostate cancer was significantly higher than that in normal tissues.