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Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response. [ABSTRACT FROM AUTHOR]

Context Medullary thyroid cancer (MTC) has a historic recurrence rate up to 50%, and surgery remains the only cure. Objective This study aims to assess factors related to recurrence and metastatic spread in MTC. Methods Retrospective chart review was performed from 1990 to 2023 at a single specialized tertiary care referral center. Descriptive analysis and regression models were used for analysis. Sixty-eight patients with MTC, who underwent surgery, were included and the main outcome measure was recurrence. Results Mean age at diagnosis was 54.9 years (42.2-64.1), 65% (n = 44) females. Lymph node and distant metastases were found in 24% (n = 16) and 4% (n = 3), respectively. RET mutations were present in 52% (n = 35): MTC risk levels were highest 6%, high 7%, and moderate 39%. Mean tumor size was 1.9 cm (1.2-3.2) and mean preoperative calcitonin was 504.4 pg/mL (133.2-1833.8). Total thyroidectomy (TT) was performed in 10 patients, TT + central neck dissection (CND) in 28, and TT + CND + lateral neck dissection (LND) in 25. On final pathology, 40% had positive central nodes and 25% had positive lateral nodes. Recurrence was 22%, median follow-up 4.7 years (1.2-28.0). Male gender (hazard ratio [HR] 5.81, P =.021), positive lateral neck nodes (HR 8.10, P =.011), and high/highest MTC risk level RET mutations (HR 8.66, P =.004) were significantly associated with recurrence. Preoperative calcitonin >2175 pg/mL was a strong predictor for distant metastasis (area under the curve [AUC] 0.893) and a good predictor for lateral neck disease (AUC 0.706). Extent of surgery was not significantly associated with recurrence (P =.634). Conclusion One of 4 patients undergoing surgery for MTC will recur. Risk factors associated with recurrence are male gender, lateral lymph node metastasis, and high/highest MTC risk level mutations, but not necessarily surgery type. Preoperative calcitonin >2175 pg/mL is suggestive of advanced disease and should prompt further evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: Peptide Receptor Radionuclide Therapy (PRRT) and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). In clinical practice, most patients receive more than one regimen, and the optimal sequence of treatments for these patients remains poorly understood. We present a real-world comparison of progression-free survival (PFS) between PRRT and CAPTEM in PNETs. Our analysis found that clinical outcomes were comparable to previously reported data in the real-world setting and were similar for both regimens. PFS for patients without extrahepatic metastases and those with MEN1, DAXX, and/or ATRX mutations might be prolonged with PRRT. Patients with grade 3 disease might fare better with CAPTEM initially. Candidates for surgical debulking or those with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to the shorter time to response. Background: Peptide Receptor Radionuclide Therapy (PRRT), a form of Radioligand Therapy (RLT), and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). Data regarding comparative efficacy are lacking. Herein, we compare the efficacy of PRRT vs. CAPTEM as second-line/beyond regimens and treatment sequencing. Methods: Clinicopathologic, radiographic, and genomic data were captured for metastatic PNETs seen in our multi-disciplinary NET clinic between 2013 and 2023. The primary outcome was progression-free survival (PFS) after progression on a previous line of systemic therapy. The secondary outcomes were objective response rate (ORR), time to response (TTR), and overall survival (OS). Results: Fifty-nine cases were included. PFS was similar in the PRRT (n = 29) and CAPTEM (n = 30) groups (PRRT = 21.90 months vs. CAPTEM = 20.03 months; HR 0.99; p = 0.97). On subgroup analysis, PRRT had longer PFS in cases without extrahepatic metastases (26.47 months vs. 17.67 months; p = 0.03) and cases with a mutation in the MEN1, DAXX, and/or ATRX genes (28.43 months vs. 18.67 months; p = 0.03). PRRT had reduced PFS in patients with grade 3 disease (7.83 months vs. 16.33 months; p = 0.02). ORR did not vary significantly (34.78% vs. 40.91%; p = 0.67). CAPTEM responders showed shorter TTR (6.03 months vs. 11.15 months; p = 0.03). In patients who received both, OS did not vary based on the sequence (HR 1.20; p = 0.75). Conclusions: PFS, ORR, and OS are similar when using PRRT vs. CAPTEM as second-line-and-beyond therapy for patients with metastatic PNETs. However, patients with MEN1, DAXX, and/or ATRX mutations or without extrahepatic metastases might better benefit from PRRT and patients with grade 3 disease from CAPTEM. Candidates for surgical debulking or with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to shorter TTR. [ABSTRACT FROM AUTHOR]

Student dropout is a major concern in studies investigating retention strategies in higher education. This study identifies which variables are important to predict student dropout, using academic data from 3583 first-year students on the Business Administration (BA) degree at the University of Barcelona (Spain). The results indicate that two variables, the percentage of subjects failed and not attended in the first semester, demonstrate significant predictive power. This has been corroborated with an additional sample of 10,784 students from three-degree programs (Law, BA, and Economics) at the Complutense University of Madrid (Spain), to assess the robustness of the results. Three different algorithms have also been utilized: neural networks, random forest, and logit. In the specific case of neural networks, the NeuralSens methodology has been employed, which is based on the use of sensitivities, allowing for its interpretation. The outcomes are highly consistent in all cases: both a simple model (logit) and more sophisticated ones (neural networks and random forest) exhibit high accuracy (correctly predicted values) and sensitivity (correctly predicted dropouts). In test set average values of 77% and 69% have been respectively achieved. In this regard, a noteworthy point is that only academic data from the university itself was used to develop the models. This ensures that there's no dependence on other personal or organizational variables, which can often be difficult to access. [ABSTRACT FROM AUTHOR]

This text explores the relationship between liturgy, sacraments, and virtue ethics. It discusses three different approaches to understanding how liturgy and sacraments shape moral character and guide ethical behavior. The first approach emphasizes the normative dimension of Christian practices and their role in addressing human needs. The second approach, known as narrative ethics, focuses on how liturgy and sacraments shape moral identity through the performance of the Christian story. The third approach views sacraments as the realization of the human telos, or ultimate goal, and emphasizes the eschatological dimension of Christian ethics. The text argues that while virtue is important, the ultimate goal of Christian life is participation in the holiness of God. [Extracted from the article]

Boron (specifically 10B) is the element of choice to shield thermal neutrons due to its large (n, α) cross‐section; however, very few polymer composites containing high boron concentrations are available. This study aimed to determine the maximum possible amount of boron that could be introduced into a polymer matrix. Diverse manufacturing techniques, ranging from additive manufacturing to compression molding, were employed to fabricate inks and filaments for 3D printing, foams, and flexible pads. Composites using siloxanes, poly(lactic acid), and acrylonitrile butadiene styrene containing up to 80 wt% boron were sucessufully fabricated. The addition of known plasticizers (polyethylene glycol) and reinforcing agents (carbon nanofibers and fumed silica) helped to overcome fabrication problems such as clogging of the printing nozzle or crumbling of compression molded parts. In addition, the thermal‐mechanical properties of these novel boron composites were determined and shown to vary according to boron concentration, presence of additives, and fabrication techniques utilized. [ABSTRACT FROM AUTHOR]

Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, amongst others, through their main protease (Mpro), which is responsible for the proteolytic cleavage of the largest part of the viral replicase polyproteins pp1a and pp1ab. Additionally, it can cleave cellular substrates, such as innate immune signaling factors, to dampen the immune response. Here, we show that MAVS is cleaved in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV), but not in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This cleavage was independent of cellular negative feedback mechanisms that regulate MAVS activation. Furthermore, MERS-CoV Mpro expression induced MAVS cleavage upon overexpression and suppressed the activation of the interferon-β (IFN-β) and nuclear factor-κB (NF-κB) response. We conclude that we have uncovered a novel mechanism by which MERS-CoV downregulates the innate immune response, which is not observed among other highly pathogenic coronaviruses. [ABSTRACT FROM AUTHOR]

Total solar eclipses (TSEs) are impressive astronomical events that have attracted people's curiosity since ancient times. Their abrupt alterations to the radiation balance have stimulated studies on "eclipse meteorology," most of them documenting events in the Northern Hemisphere while only one TSE (23 November 2003) has been described over Antarctica. On 4 December 2021--just a few days before the austral summer solstice--the moon blocked the sun over the austral high latitudes, with the path of totality arching from the Weddell Sea to the Amundsen Sea, thus producing a ~2-min central TSE. In this work we present high-resolution meteorological observations from Union Glacier Camp (80°S, 83°W), the only location with a working station under totality, and South Pole station. These observations were complemented with meteorological records from 37 surface stations across Antarctica. Notably, the largest cooling (~5°C) was observed over the East Antarctic dome, where obscurity was ~85% while many sectors experienced insignificant temperature changes. This heterogenous cooling distribution, at odds with the seemingly homogeneous land surface of Antarctica, is partially captured by a simple radiative model. To further diagnose the effect of the eclipse on the surface meteorology, we ran multiple pairs of simulations (eclipse enabled and disabled) using the Weather Research and Forecasting (WRF) Model. The overall pattern and magnitude of the simulated cooling agree well with the observations and reveal that, in addition to the solar radiation deficit and cloud cover, low-level winds and the height of the planetary boundary layer are key determinants of the temperature changes and their spatial variability. [ABSTRACT FROM AUTHOR]

The central premise of this article is that synodality ought to be grounded in the Eucharist. The author explores the implications of this claim in the areas of ecclesiology and ethics. On the side of ecclesiology, the author argues that the Eucharist is the ritual and theological center of a synodal church. In the context of its own life, considered not only at an abstract theological level but at a practical and political level as well, the church cannot be synodal if it is not attentive to its Eucharistic origins. Synodality is the key in which communion is realized. The author discusses this idea in the context of the Eucharist Revival in the United States and in connection to baptism and the ecclesiology of the People of God. On the side of ethics, the author develops an account of synodality as a virtue. Synodality is the virtue that shapes the church and its members in order to realize communion. Its object is the right use of power. An ethics of synodality, the author argues, entails both reform in the church itself and a commitment on the part of the church and its members to a politics of the universal common good and the building of a just social order. [ABSTRACT FROM AUTHOR]

Although fumed silica/siloxane suspensions are commonly employed in additive manufacturing technology, the interplay between shelf life, storage conditions, and printability has yet to be explored. In this work, direct ink writing (DIW) was used to print unique three-dimensional structures that required suspensions to retain shape and form while being printed onto a substrate. Suspensions containing varying concentrations of hydrophobic and hydrophilic silica were formulated and evaluated over a time span of thirty days. Storage conditions included low (8%) and high (50%) relative humidity and temperatures ranging from 4 °C to 25 °C. The shelf life of the suspensions was examined by comparing the print quality of pristine and aged samples via rheology, optical microscopy, and mechanical testing. Results showed a significant decrease in printability over time for suspensions containing hydrophilic fumed silica, whereas the printability of suspensions containing hydrophobic fumed silica remained largely unchanged after storage. The findings in this work established the following recommendations for extending the shelf life and printability of suspensions commonly used in DIW technology: (1) higher fumed silica concentrations, (2) low humidity and low temperature storage environments, and (3) the use of hydrophobic fumed silica instead of hydrophilic fumed silica. [ABSTRACT FROM AUTHOR]

In theory, the application of fertilizers is a relationship between the requirement of the crop and the content already present in the soil. However, in acidic soils, it is estimated that only 10–15% of the total phosphorus (P) applied is available to plants, requiring higher doses. As the importance of P in plants is notorious and unquestionable, being involved in the regulation of photosynthesis and plant development, there are several alternatives to increase its application efficiency. However, there is a lack of research that seeks to understand how different genotypes of the same species respond to different availability of P. The aim of this study was to evaluate the development of maize varieties under different conditions of P availability, thus bringing a new perspective for future studies that seek to increase the availability of P to plants. A randomized block experiment was carried out in a factorial scheme with five maize hybrids and five P availability, with four replications. The plants were evaluated for gas exchange, chlorophyll a fluorescence, chloroplast pigment content, shoot length and biomass accumulation. In low availability, there is a negative feedback control of photoassimilates export, which results in reduced photosynthesis, growth and biomass accumulation. This reduction in growth may also be associated with the hormonal control of plants. Despite the well-established relationship between photosynthesis and biomass accumulation, it is not always possible to establish a parallel between the two processes, depending on the genetic composition. [ABSTRACT FROM AUTHOR]

A flight attendant experiences the grandeur of traveling around the world while being paid, having the means to travel across borders for free, having insurance and safety, meeting diverse groups of people, and experiencing new cultures. As the aspirants are keen to accomplish their future occupation, there are also several perceived hindrances that become an obstacle to their decision to meet airline industry standards. This study aims to evaluate the credentials and criteria imposed by airlines to influence individuals' decisions to pursue a career in the airline industry as a flight attendant. This study employed a descriptive correlation using a convenience approach with 346 respondents from two ICEaccredited universities in Manila. The study reveals that aspiring flight attendants have a high level of career confidence due to the unique and diverse benefits and opportunities of being a flight attendant. Moreover, there is a significant relationship between aspirants' perceptions of their qualifications and their career decisions. The Kruskal-Wallis H Test showed that there is no notable difference in how the aspirants perceive the qualifications of being a flight attendant when they are grouped based on their year level. Using Spearman's rho correlation coefficient, it indicates a significant and moderate relationship between the physical qualifications and the career decision, while a moderately significant correlation exists between the academic qualifications and the career decision of the aspirants. This study fills the gap by fostering awareness among aspiring flight attendants' decisionmaking processes to be qualified, enhancing their chances of employability, and The study also revealed that qualifications are necessary for an airline to achieve excellence and professionalism in the workplace and to preserve its reputation. Creating impressions that will benefit the airline company. Overall, the airline industry's physical, academic, and skills qualifications have a significant influence on the career choice of the aspirants, which can help them decide their future profession. [ABSTRACT FROM AUTHOR]

Increasing the efficiency of photosynthesis in sugarcane canopies is the key for improving crop yield. Herein, we evaluated the photosynthetic performance along the canopy of ten sugarcane cultivars and three Saccharum species. Canopy morphological traits were evaluated, and leaf gas exchange was measured in the first (sun-exposed, +1) and the fourth (shaded, +4) fully expanded leaves and under low- and high-light conditions. Similar photosynthetic capacity was found in leaves +1 and +4 under high light in genotypes with a high leaf area index and a high fraction of the sky blocked by the foliage (> 85%). Interestingly, such canopy characteristics cause low light availability to leaves +4, suggesting the photosynthetic acclimation of these leaves to self-shading in some genotypes. We highlight IACCTC06-8126 and CTC4 as those genotypes with higher canopy photosynthetic capacity, presenting high leaf area, high photosynthetic rates in sun-exposed leaves, and high responsiveness of shaded leaves to increasing light availability. [ABSTRACT FROM AUTHOR]

Purpose of Review: Intravitreal anti-vascular endothelial growth factor (VEGF) agents are used routinely in the management of neovascular conditions including proliferative diabetic retinopathy and diabetic macular edema. While the efficacy of anti-VEGF agents has been well-validated, their ocular and systemic adverse events should always be considered and discussed with patients. The aim of this review is to discuss the most recent literature reports regarding the various ocular and systemic adverse events associated with intravitreal anti-VEGF treatment in diabetic retinopathy. Recent Findings: The most frequently reported adverse ocular events include subconjunctival hemorrhage, vitreous hemorrhage, increased intraocular pressure, uveitis, endophthalmitis, ocular surface disease, and traumatic cataract. Subconjunctival hemorrhage and vitreous hemorrhage are the most common ocular adverse events reported with intravitreal anti-VEGF treatment. The most serious (though rare) ocular adverse events include endophthalmitis and rhegmatogenous retinal detachment. A consensus regarding the association of systemic adverse events (such as myocardial infarction, stroke, and death) with intravitreal anti-VEGF treatments has not been established. Summary: Intravitreal anti-VEGF therapy is used in the treatment of diabetic retinopathy, macular degeneration, and other diseases. These agents are associated with a variety of ocular and systemic adverse events that ophthalmologists should always consider. [ABSTRACT FROM AUTHOR]

Study Question: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children?Summary Answer: In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children.What Is Known Already: DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day.Study Design, Size, Duration: This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception).Participants/materials, Setting, Methods: Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing.Main Results and the Role Of Chance: No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10-7), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age).Limitations, Reasons For Caution: This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results.Wider Implications Of the Findings: This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort.Study Funding/competing Interest(s): This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Somatic MEN1 mutations occur in up to 50% of pancreatic neuroen docrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond be tter to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1- deficient cells and linked these findings to a defect in homologo us recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function. [ABSTRACT FROM AUTHOR]

Von Hippel–Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018‐2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL‐related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL‐related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL‐related pancreatic manifestations. Pancreatic neuroendocrine tumors that develop in the context of von Hippel–Lindau (VHL) disease have a distinct natural history. Other VHL manifestations complicate metastatic risk and their management. An international committee of experts in VHL‐related pancreatic neuroendocrine tumors has developed a set of recommendations for the management of these unique neoplasms to set a standard of care for expert centers worldwide. [ABSTRACT FROM AUTHOR]

Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer's disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer's Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed. [ABSTRACT FROM AUTHOR]

Background: Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells. Methods: Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral). Results: SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral. Conclusions: This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection. [ABSTRACT FROM AUTHOR]

The Viking press exercise is an upper-body strength and power movement with several potential benefits for athletes. The aim of this article is to describe proper exercise technique and introduce variations for the Viking press. [ABSTRACT FROM AUTHOR]

High performance computing simulations often produce datasets defined over unstructured grids. Those grids allow for the local refinement of the resolution and can accommodate arbitrary boundary geometry. From a visualization standpoint, however, such grids have a high storage cost, require special spatial data structures, and make the computation of high-quality derivatives challenging. Rectilinear grids, in contrast, have a negligible memory footprint and readily support smooth data reconstruction, though with reduced geometric flexibility. The present work is concerned with the creation of an accurate reconstruction of large unstructured datasets on rectilinear grids. We present an efficient method to automatically determine the geometry of a rectilinear grid upon which a low-error data reconstruction can be achieved with a given reconstruction kernel. Using this rectilinear grid, we address the potential ill-posedness of the data fitting problem, as well as the necessary balance between smoothness and accuracy, through a bi-level smoothness regularization. To tackle the computational challenge posed by very large input datasets and high-resolution reconstructions, we propose a block-based approach that allows us to obtain a seamless global approximation solution from a set of independently computed sparse least-squares problems. Results are presented for several 3D datasets that demonstrate the quality of the visualization results that our reconstruction enables, at a greatly reduced computational and memory cost. [ABSTRACT FROM AUTHOR]

Emotional Intelligence (EQ) is the capacity for identifying, evaluating, controlling, and effectively expressing emotions. A person with a high EQ is better at communicating, managing anxiety and stress, resolving conflicts, improving relationships, empathizing with others, and overcoming life's obstacles. Emotional intelligence has an effect on life quality since it has an effect on human behavior and relationships (McPheat, S. 2010). Developing a high EQ can assist determine our success; it can also influence our choices by opening us possibilities we would not have explored before. The way your child controls his or her emotions has an effect on everything from his or her connections with peers to academic success. Students who have a greater level of emotional intelligence are better able to control their emotions and are more empathetic toward others. This can assist them in developing more self-motivation and more effective communication skills--both of which are necessary for kids to develop into more confident learners. On the other hand, students who lack emotional intelligence may develop a lack of connection to school, which can have a detrimental effect on academic success. The purpose of this paper is to examine college students' perspectives on emotional intelligence in higher education. Globally, numerous changes in the educational system have created new demands for teachers. Nowadays, instructors serve as a mentor as well as an authority figure in the classroom. Thus, emotions are crucial to the teaching and learning processes. The article accentuates Emotional intelligence being neither a polar opposite of intelligence nor the conflict between the mind and the heart; rather, deems it to be a singular junction of the two. This research articulates the key role of emotional intelligence in the academic process from the student's or learner's perspective (Stys, Y. & Brown, 2004). [ABSTRACT FROM AUTHOR]

The current nursing shortage and high turnover is of great concern in many countries because of its impact upon the efficiency and effectiveness of any health-care delivery system. Recruitment and retention of nurses are persistent problems associated with job satisfaction. This paper analyses the growing literature relating to job satisfaction among nurses and concludes that more research is required to understand the relative importance of the many identified factors to job satisfaction. It is argued that the absence of a robust causal model incorporating organizational, professional and personal variables is undermining the development of interventions to improve nurse retention. Nurses job satisfaction is an important issue because of its impact on the quality of the nursing job. Therefore, it receives a lot of attention in the international nursing literature but insight into the sources of nurses job satisfaction is yet insufficient, in particular for sources related to organizational structure. Job satisfaction has become a critical issue for healthcare organizations, particularly in nursing, because of the shortage of nursing labor, the effect on patient care, and the associated costs. This study explores the factors that influence the level of job satisfaction of nurses working in one regional hospital [ABSTRACT FROM AUTHOR]

Background: Inversion ankle sprains, or lateral ankle sprains, often result in symptomatic lateral ankle instability, and some patients need lateral ankle ligament reconstruction to reduce pain, improve function, and prevent subsequent injuries. Although anatomically reconstructed ligaments should behave in a biomechanically normal manner, previous studies have not measured the strain patterns of the anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) after anatomical reconstruction. This study aimed to measure the strain patterns of normal and reconstructed ATFL and CFLs using the miniaturization ligament performance probe (MLPP) system.Methods: The MLPP was sutured into the ligamentous bands of the ATFLs and CTLs of three freshly frozen cadaveric lower-extremity specimens. Each ankle was manually moved from 15° dorsiflexion to 30° plantar flexion, and a 1.2-N m force was applied to the ankle and subtalar joint complex.Results: The normal and reconstructed ATFLs exhibited maximal strain (100) during supination in three-dimensional motion. Although the normal ATFLs were not strained during pronation, the reconstructed ATFLs demonstrated relative strain values of 16-36. During the axial motion, the normal ATFLs started to gradually tense at 0° plantar flexion, with the strain increasing as the plantar flexion angle increased, to a maximal value (100) at 30° plantar flexion; the reconstructed ATFLs showed similar strain patterns. Further, the normal CFLs exhibited maximal strain (100) during plantar flexion-abduction and relative strain values of 30-52 during dorsiflexion in three-dimensional motion. The reconstructed CFLs exhibited the most strain during dorsiflexion-adduction and demonstrated relative strain values of 29-62 during plantar flexion-abduction. During the axial motion, the normal CFLs started to gradually tense at 20° plantar flexion and 5° dorsiflexion.Conclusion: Our results showed that the strain patterns of reconstructed ATFLs and CFLs are not similar to those of normal ATFLs and CFLs. [ABSTRACT FROM AUTHOR]

Effective provisions of preparedness and response are necessary to protect human life, health, property, and the environment in any nuclear and radiological emergency. Recently, the International Commission on Radiological Protection recognized the need to provide more quantitative guidance on environmental radiation protection to integrate these analyses. A required assessment is a correlation between dose and its effects in non-human biota. Plants are highly sensitive environmental monitors for the assessment of potentially genotoxic agents and avoid the controversial use of animal models. The Allium test is commonly used to assess genotoxicity for a wide variety of chemical and physical factors, as it allows for estimates of possible DNA damage in eukaryotes in general, including humans. In this work, onion (Allium cepa) seedlings were exposed to 20–200 mGy of α -radiation. We studied the possibility of using cytogenetic analyses of irradiated onion cells to determine the biological dose. It was observed that the increase in the frequencies of chromosomal aberrations, mitotic abnormalities, and micronuclei occurred proportional to the radiation dose, but a reduction in cytological damage was observed from 100 mGy, suggesting the onset of cytotoxic activity. Our research shows the potential of Allium cepa as a sensitive support system for dosimetry, detection, and screening of cellular effects produced by low doses of environmental radiation. [ABSTRACT FROM AUTHOR]

Osteoid osteoma is a painful, benign and common bone tumor that is prevalent in young adults. The typical clinical presentation consists of pain that becomes worse at night and is relieved by nonsteroidal anti-inflammatory drugs. The most common imaging finding is a lytic lesion, known as a nidus, with variable intralesional mineralization, accompanied by bone sclerosis, cortical thickening and surrounding bone marrow edema, as well as marked enhancement with intravenous contrast injection. When the lesion is located in typical locations (intracortical bone and the diaphyses of long bones), both characteristic clinical and radiological features are diagnostic. However, osteoid osteoma is a multifaceted pathology that can have unusual presentations, such as intraarticular osteoid osteoma, epiphyseal location, lesions at the extremities and multicentric nidi, and frequently present atypical clinical and radiological manifestations. In addition, many conditions may mimic osteoid osteoma and vice versa, leading to misdiagnosis. Therefore, it is essential to understand these musculoskeletal diseases and their imaging findings to increase diagnostic accuracy, enable early treatment and prevent poor prognosis. [ABSTRACT FROM AUTHOR]

Emotional Intelligence (EQ) is the capacity for identifying, evaluating, controlling, and effectively expressing emotions. A person with a high EQ is better at communicating, managing anxiety and stress, resolving conflicts, improving relationships, empathizing with others, and overcoming life's obstacles. Emotional intelligence has an effect on life quality since it has an effect on human behavior and relationships (McPheat, S. 2010). Developing a high EQ can assist determine our success; it can also influence our choices by opening us possibilities we would not have explored before. The way your child controls his or her emotions has an effect on everything from his or her connections with peers to academic success. Students who have a greater level of emotional intelligence are better able to control their emotions and are more empathetic toward others. This can assist them in developing more selfmotivation and more effective communication skills--both of which are necessary for kids to develop into more confident learners. On the other hand, students who lack emotional intelligence may develop a lack of connection to school, which can have a detrimental effect on academic success. The purpose of this paper is to examine college students' perspectives on emotional intelligence in higher education. Globally, numerous changes in the educational system have created new demands for teachers. Nowadays, instructors serve as a mentor as well as an authority figure in the classroom. Thus, emotions are crucial to the teaching and learning processes. The article accentuates Emotional intelligence being neither a polar opposite of intelligence nor the conflict between the mind and the heart; rather, deems it to be a singular junction of the two. [ABSTRACT FROM AUTHOR]

Identifying the genes causing male infertility is important to increase our biological understanding as well as the diagnostic yield and clinical relevance of genetic testing in this disorder. While significant progress has been made in some areas, mainly in our knowledge of the genes underlying rare qualitative sperm defects, the same cannot be said for the genetics of quantitative sperm defects. Technological advances and approaches in genomics are critical for the process of disease gene identification. In this review we highlight the impact of various technological developments on male infertility gene discovery as well as functional validation, going from the past to the present and the future. In particular, we draw attention to the use of unbiased genomics approaches, the development of increasingly relevant functional assays and the importance of large-scale international collaboration to advance disease gene identification in male infertility. [ABSTRACT FROM AUTHOR]

Background: We sought to identify immunoglobin G autoantibodies predictive of early treatment response to methotrexate, the recommended first-line therapy for patients with newly diagnosed rheumatoid arthritis, and to the interleukin-6 receptor inhibitor biologic tocilizumab, initiated as the first disease-modifying anti-rheumatic drug. Materials and methods: In baseline sera of a subset of patients with newly diagnosed rheumatoid arthritis in the U-Act-Early study, selected based on specific responder/non-responder criteria using the Disease Activity Score assessing 28 joints (DAS28) within the first 20 weeks, we measured immunoglobin G antibody reactivity against 463 protein antigens and performed supervised cluster analysis to identify predictive autoantibodies for treatment response. The analysis subset comprised 56 patients in the methotrexate arm (22 responders, 34 non-responders) and 50 patients in the tocilizumab arm (34 responders, 16 non-responders). For comparison, these analyses were also performed in 50 age- and gender-matched healthy controls. Results: Increased reactivity in responders versus non-responders was found in the methotrexate arm against two antigens—DOT1-like histone lysine methyltransferase (p = 0.009) and tropomyosin (p = 0.003)—and in the tocilizumab arm against one antigen—neuro-oncological ventral antigen 2 (p = 0.039). Decreased reactivity was detected against two antigens in the methotrexate arm—G1 to S phase transition 2 (p = 0.023) and the zinc finger protein ZPR1 (p = 0.021). Reactivity against the identified antigens was not statistically significant in either treatment arm for patients with rheumatoid factor–positive versus–negative or anti-cyclic citrullinated test–positive versus test–negative rheumatoid arthritis (p ≥ 0.06). Conclusions: Comprehensive profiling of baseline sera revealed several novel immunoglobin G autoantibodies associated with early treatment response to methotrexate and to tocilizumab in disease-modifying anti-rheumatic drug-naive patients with rheumatoid arthritis. These findings could eventually yield clinically relevant predictive markers, if corroborated in different patient cohorts, and may facilitate future benefit in personalised healthcare. [ABSTRACT FROM AUTHOR]

The current clinical case was reported from Wayanad district of Kerala. The animal was a nine-year-old female chestnut pony weighing about 90 kg. Clinical signs observed were recumbency, anorexia, dehydration, rolling, kicking at the abdomen, tachycardia, abdominal distension, tympanic sounds on abdominal percussion, and frequent attempts to urinate and defecate. Treatment by using Flunixin meglumine at a dose rate of 1.1 mg/kg bodyweight Ringer's lactate, dextrose normal saline intravenously, ranitidine intramuscularly at a dose rate of 2 mg/kg bodyweight along with nasogastric intubation and coconut oil infusions successfully controlled the signs of colic and the animal recovered uneventfully. [ABSTRACT FROM AUTHOR]

Background: Human epidermal growth factor receptor-4 (HER4) and yes-associated protein-1 (YAP) are candidate therapeutic targets in oncology. YAP's transcriptional coactivation function is modulated by the HER4 intracellular domain (HER4-ICD) in vitro, but the clinical relevance of this has not been established. This study investigated the potential for targeting the HER4-YAP pathway in brain metastatic breast cancer. Methods: We performed immuno-phenotypic profiling of pathway markers in a consecutive breast cancer series with 25 years of clinical follow up (n = 371), and patient-matched breast and metastatic brain tumours (n = 91; 30 pairs). Results: Membrane localisation of phospho-HER4 [pHER4(Y1162)] was infrequent in primary breast cancer, but very frequent in brain metastases (5.9% versus 75% positive), where it was usually co-expressed with pHER3(Y1289) (p < 0.05). The presence of YAP in tumour cell nuclei was associated directly with nuclear pERK5(T218/Y210) (p = 0.003). However, relationships with disease-specific survival depended on oestrogen receptor (ER) status. Nuclear pYAP(S127) was associated with smaller, good prognostic ER+ breast tumours (log-rank hazard-ratio 0.53; p = 9.6E−03), but larger, poor prognostic triple-negative cancers (log-rank hazard-ratio 2.78; p = 1.7E−02), particularly when co-expressed with nuclear HER4-ICD (p = 0.02). This phenotype was associated with stemness and mitotic instability markers (vimentin, SOX9, ID1, SPAG5, TTK, geminin; p < 0.05). YAP expression in brain metastases was higher than matched primary tumours; specifically, nuclear pYAP(S127) in ER-negative cases (p < 0.05). Nuclear YAP was detected in ~70% of ER-negative, HER4-activated brain metastases. Discussion: Our findings suggest that the canonical-mechanism where Hippo pathway-mediated phosphorylation of YAP ostensibly excludes it from the nucleus is dysfunctional in breast cancer. The data are consistent with pYAP(S127) having independent transcriptional functions, which may include transducing neuregulin signals in brain metastases. Consistent with mechanistic studies implicating it as an ER co-factor, nuclear pYAP(S127) associations with breast cancer clinical outcomes were dependent on ER status. Conclusion: Preclinical studies investigating HER4 and nuclear YAP combination therapy strategies are warranted. [ABSTRACT FROM AUTHOR]

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence. [ABSTRACT FROM AUTHOR]

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence. [ABSTRACT FROM AUTHOR]

Background: There are few reports on the detailed biomechanics of the deltoid ligament, and no studies have measured the biomechanics of each ligamentous band because of the difficulty in inserting sensors into the narrow ligaments. This study aimed to measure the strain pattern of the deltoid ligament bands directly using a Miniaturization Ligament Performance Probe (MLPP) system.Methods: The MLPP was sutured into the ligamentous bands of the deltoid ligament in 6 fresh-frozen lower extremity cadaveric specimens. The strain was measured using a round metal disk (clock) fixed on the plantar aspect of the foot. The ankle was manually moved from 15° dorsiflexion to 30° plantar flexion, and a 1.2-N-m force was applied to the ankle and subtalar joint complex. Then the clock was rotated every 30° to measure the strain of each ligamentous band at each endpoint.Results: The tibionavicular ligament (TNL) began to tense at 10° plantar flexion, and the tension becomes stronger as the angle increased; the TNL worked most effectively in plantar flex-abduction. The tibiospring ligament (TSL) began to tense gradually at 15° plantar flexion, and the tension became stronger as the angle increased. The TSL worked most effectively in abduction. The tibiocalcaneal ligament (TCL) began to tense gradually at 0° dorsiflexion, and the tension became stronger as the angle increased. The TCL worked most effectively in pronation (dorsiflexion-abduction). The superficial posterior tibiotalar ligament (SPTTL) began to tense gradually at 0° dorsiflexion, and the tension became stronger as the angle increased, with the SPTTL working most effectively in dorsiflexion.Conclusion: Our results show the biomechanical function of the superficial deltoid ligament and may contribute to determining which ligament is damaged during assessment in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: In rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes.Objectives: To determine if inclusion of patients on background GC use influenced efficacy and safety outcomes of RA randomised clinical trials on initiation of tocilizumab (TCZ) or adalimumab (ADA) or methotrexate (MTX) monotherapy.Methods: Data of four double-blind RA randomised controlled trials (AMBITION, ACT-RAY, ADACTA and FUNCTION) with in total four TCZ, one ADA and two MTX monotherapy arms were analysed. Analyses of covariance of changes from baseline to week 24 in efficacy endpoints and radiographic progression up to week 104 were performed, correcting for relevant covariates. Incidence rates of serious adverse events (SAEs) were assessed.Results: No statistically significant differences were found in efficacy parameters between background GC users and non-GC users, except for less radiographic progression associated with GC usage in one MTX arm. SAE rates were not statistically significantly different between GC users and non-GC users in the treatment arms.Conclusion: No effect of including patients on background GC treatment on efficacy and safety trial outcomes was found, with the exception of reduced radiological joint damage in one MTX arm. [ABSTRACT FROM AUTHOR]

Background: The role of perioperative systemic therapy (PST) in the management of localized pancreatic neuroendocrine neoplasms (PanNEN) is unclear. Objectives: We aimed to evaluate the benefit of PST compared to surgery alone (SA) in patients with localized PanNEN. Method: We selected patients with stages I–III PanNEN who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who had both PST and surgical resection were matched with patients who received SA by propensity score at 1-to-1 ratio with nearest neighbor method. Results: Four thousand eight hundred and ninety-two patients were included in this study with median age of 60 years. Factors associated with significant more use of PST compared to SA included age <65 years, community medical facilities, grade 3 tumor, tumor in the pancreatic head, T34 tumor, and N1 tumor. Three hundred and one PST patients were matched with 301 SA patients. In the matched cohort, the PST group had significantly shorter overall survival (OS) compared to the SA group (median overall both not reached, p = 0.037). This finding was confirmed by multivariable Cox proportional hazards regression in the original cohort (hazard ratio [HR] 1.45, 95% CI 1.11–1.89, p = 0.006). Subgroup analyses showed that adjuvant therapy was not associated with improved OS in grades 1–2 PanNEN (HR 2.03, 95% CI 1.31–3.16, p = 0.002). Conclusions: PST stratified by grade and neoadjuvant or adjuvant therapy compared to SA was not associated with improved OS in patients with localized PanNEN. PST for localized PanNEN should be used with caution until prospective data are available. [ABSTRACT FROM AUTHOR]

Background: The only potential cure for neuroendocrine tumors (NETs) is operative resection, which may also offer a survival benefit for advanced disease. We aimed to assess the role of 68Ga-DOTATATE PET/CT in preoperative planning and compared its performance to CT with IV contrast and MRI with Eovist®, for abdominal NETs. Methods: Records of patients who underwent 68Ga-DOTATATE PET/CT in addition to MRI with Eovist® and/or CT with IV contrast were retrospectively evaluated. The effect of imaging findings on surgical management and characteristics of detected lesions were analyzed. Descriptive statistics were used. Results: Of 21 patients who underwent 68Ga-DOTATATE PET/CT prior to surgical resection, five (24%) had a change in surgical management due to findings. In three patients, 68Ga-DOTATATE PET/CT identified the primary tumor. In two patients, 68Ga-DOTATATE PET/CT helped clarify equivocal hepatic lesions seen on MRI with Eovist®. MRI with Eovist® had the highest number of lesions found (median 13, versus 9 on CT and 9.5 on 68Ga-DOTATATE PET/CT). DOTATATE-avid lesions were on average larger than lesions seen only on MRI with Eovist® (1.6 cm versus 0.6 cm, p = 0.0002). The optimal cutoff point for detection by 68Ga-DOTATATE PET/CT was a size of 0.95 cm, with a sensitivity of 56% and specificity of 98%. Conclusions: Preoperative 68Ga-DOTATATE PET/CT is useful only in a subset of patients undergoing surgical resection for NETs. MRI with Eovist® is superior at identifying liver metastases when compared to 68Ga-DOTATATE PET/CT and should therefore be used routinely before hepatic cytoreduction of NETs. [ABSTRACT FROM AUTHOR]

Study Question: Do all regions of the paternal genome within the gamete display equivalent vulnerability to oxidative DNA damage?Summary Answer: Oxidative DNA damage is not randomly distributed in mature human spermatozoa but is instead targeted, with particular chromosomes being especially vulnerable to oxidative stress.What Is Known Already: Oxidative DNA damage is frequently encountered in the spermatozoa of male infertility patients. Such lesions can influence the incidence of de novo mutations in children, yet it remains to be established whether all regions of the sperm genome display equivalent susceptibility to attack by reactive oxygen species.Study Design, Size, Duration: Human spermatozoa obtained from normozoospermic males (n = 8) were split into equivalent samples and subjected to either hydrogen peroxide (H2O2) treatment or vehicle controls before extraction of oxidized DNA using a modified DNA immunoprecipitation (MoDIP) protocol. Specific regions of the genome susceptible to oxidative damage were identified by next-generation sequencing and validated in the spermatozoa of normozoospermic males (n = 18) and in patients undergoing infertility evaluation (n = 14).Participants/materials, Setting, Methods: Human spermatozoa were obtained from normozoospermic males and divided into two identical samples prior to being incubated with either H2O2 (5 mm, 1 h) to elicit oxidative stress or an equal volume of vehicle (untreated controls). Alternatively, spermatozoa were obtained from fertility patients assessed as having high basal levels of oxidative stress within their spermatozoa. All semen samples were subjected to MoDIP to selectively isolate oxidized DNA, prior to sequencing of the resultant DNA fragments using a next-generation whole-genomic sequencing platform. Bioinformatic analysis was then employed to identify genomic regions vulnerable to oxidative damage, several of which were selected for real-time quantitative PCR (qPCR) validation.Main Results and the Role Of Chance: Approximately 9000 genomic regions, 150-1000 bp in size, were identified as highly vulnerable to oxidative damage in human spermatozoa. Specific chromosomes showed differential susceptibility to damage, with chromosome 15 being particularly sensitive to oxidative attack while the sex chromosomes were protected. Susceptible regions generally lay outside protamine- and histone-packaged domains. Furthermore, we confirmed that these susceptible genomic sites experienced a dramatic (2-15-fold) increase in their burden of oxidative DNA damage in patients undergoing infertility evaluation compared to normal healthy donors.Limitations, Reasons For Caution: The limited number of samples analysed in this study warrants external validation, as do the implications of our findings. Selection of male fertility patients was based on high basal levels of oxidative stress within their spermatozoa as opposed to specific sub-classes of male factor infertility.Wider Implications Of the Findings: The identification of genomic regions susceptible to oxidation in the male germ line will be of value in focusing future analyses into the mutational load carried by children in response to paternal factors such as age, the treatment of male infertility using ART and paternal exposure to environmental toxicants.Study Funding/competing Interest(s): Project support was provided by the University of Newcastle's (UoN) Priority Research Centre for Reproductive Science. M.J.X. was a recipient of a UoN International Postgraduate Research Scholarship. B.N. is the recipient of a National Health and Medical Research Council of Australia Senior Research Fellowship. Authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

Objectives: Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA.Methods: Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders.Results: DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: -0.62 (95% CI -1.14 to -0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies.Conclusions: In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs. [ABSTRACT FROM AUTHOR]

Malignant tumours show a marked degree of morphological, molecular and proteomic heterogeneity. This variability is closely related to microenvironmental factors and the location of the tumour. The activation of genetic alterations is very tissue‐dependent and only few tumours have distinct genetic alterations. Importantly, the activation state of proteins and signaling factors is heterogeneous in the primary tumour and in metastases and recurrences. The molecular diagnosis based only on genetic alterations can lead to treatments with unpredictable responses, depending on the tumour location, such as the tumour response in melanomas versus colon carcinomas with BRAF mutations. Therefore, we understand that the correct evaluation of tumours requires a system that integrates both morphological, molecular and protein information in a clinical and pathological context, where intratumoral heterogeneity can be assessed. Thus, we propose the term 'tissunomics', where the diagnosis will be contextualised in each tumour based on the complementation of the pathological, molecular, protein expression, environmental cells and clinical data. [ABSTRACT FROM AUTHOR]

Background: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.Methods: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools.Results: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs.Conclusions: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs. [ABSTRACT FROM AUTHOR]