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The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.

Jupiter’s disc is bright in X-rays as H2 molecules in the atmosphere are very effective at scattering solar X-rays. K-shell fluorescence from carbon atoms in atmospheric methane is thought to also provide a minor contribution. XMM–Newton has now observed Jupiter over a span of nearly two solar cycles from 2003 to 2021, offering the opportunity to determine whether Jupiter’s disc emissions are driven by solar activity or not. We compare the count rates of X-rays of energies 0.2–10.0, 0.2–2.0, 2.1–5.0, and 5.1–10.0 keV from the planet’s equatorial region, with the sunspot number and F10.7 adjusted solar radio flux. The respective Pearson’s correlation coefficients for both are 0.88/0.84, 0.86/0.83, 0.40/0.34, and 0.29/0.22 for each energy demonstrating that the low-energy X-ray disc emissions are indeed controlled by the Sun’s activity. This relationship is less clear for the higher energy emissions, raising questions around the source of these emissions.

The aim of this study was to develop an improved understanding of the delayed immunologic effects of acute total body irradiation (TBI) using a diverse cohort of nonhuman primates as a model for an irradiated human population.Immune recovery was evaluated in 221 rhesus macaques either left unirradiated (n = 36) or previously irradiated (n = 185) at 1.1 to 8.5 Gy TBI (median, 6.5 Gy) when aged 2.1 to 15.5 years (median, 4.2 years). Blood was drawn annually for up to 5 years total between 0.5 and 14.3 years after exposure. Blood was analyzed by complete blood count, immunophenotyping of monocytes, dendritic cells (DC) and lymphocytes by flow cytometry, and signal joint T-cell receptor exclusion circle quantification in isolated peripheral blood CD4 and CD8 T cells. Animals were categorized by age, irradiation status, and time since irradiation. Sex-adjusted means of immune metrics were evaluated by generalized estimating equation models to identify cell populations altered by TBI.Overall, the differences between irradiated and nonirradiated animals were subtle and largely restricted to younger animals and select cell populations. Subsets of monocytes, DC, T cells, and B cells showed significant interaction effects between radiation dose and age after adjustment for sex. Irradiation at a young age caused transient increases in the percentage of peripheral blood myeloid DC and dose-dependent changes in monocyte balance for at least 5 years after TBI. TBI also led to a sustained decrease in the percentage of circulating memory B cells. Young irradiated animals exhibited statistically significant and prolonged disruption of the naïve/effector memory/central memory CD4 and CD8 T-cell equilibrium and exhibited a dose-dependent increase in thymopoiesis for 2 to 3 years after exposure.This study indicates TBI subtly but significantly alters the circulating proportions of cellular mediators of adaptive immune memory for several years after irradiation, especially in macaques under 5 years of age and those receiving a high dose of radiation.

Background Monitoring trends in the burden of illness and injury attributable to work is key in assessing occupational health hazards; however, New Brunswick does not participate in the Canadian National Ambulatory Care Reporting System which itself does not collect details of occupation and industry. Aims We set out to determine the proportion of emergency department attendances that were attributable to a work-related cause. We also wanted to evaluate the recording of occupation in the electronic health record system, and to describe the characteristics of patients with a work-related presentation. Methods A retrospective observational study over a 1-year period was conducted using an administrative database obtained from Canadian Emergency Department Information System. Descriptive statistics are used to present the analysis of categorical and continuous data. Results A total of 49 365 patients were included for analysis. Two per cent of patients presented with a self-reported work-related condition. Health care and social assistance, construction, retail trade and manufacturing were the most common industries reported by patients. Conclusions This study found the rate of work-related medical conditions to be substantially less than expected, and that occupation was not captured for any patients presenting to the emergency department with a work-related condition, despite a field being available in the electronic health record registration system. We were able to analyse the industry sectors for work-related presentations. The recording and coding of occupation and industry would significantly benefit occupational epidemiology in emergency medicine as well as potentially improving patient outcomes and health system efficiencies.

Ice hockey is a high-speed sport played on a slippery ice surface, using sharp skate blades, rigid sticks with a hard rubber puck, and allowing full-force physical contact that includes body checking and fighting. Although many of the same injuries to the hand and wrist occur that are seen in other sports, there is a higher frequency of certain injuries in the hockey athlete due to the forces involved, the way the hockey stick is gripped, torqued, and used, and the fact that players can slash one another with their sticks. Beyond timely and accurate management of the injury itself, the role of the consultant hand surgeon in hockey encompasses mastery of the intangible skills in the art and humanity of medical care. Injury to the hockey athlete sets in motion a dynamic process that involves many stakeholders who each require your knowledge of how this will affect the hockey athlete's immediate and long-term health, how long they may be out of competition, and the kind of treatments, splints and equipment modifications that could help foster the earliest return-to-play in a safe manner. The consultant hand surgeon needs the ability to communicate information at a high level to team physicians and trainers while remaining nimble enough to simplify that information for general managers, coaches, agents, and athletes. The role demands commitment in time and flexibility, remaining open to gray areas in treatment options, possessing a creative mindset for problem-solving, and the ability to quickly assimilate vast amounts of information to provide a risk assessment of short and long-term implications the injury presents to both the player and the team.

Background: Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review, we give an overview of all currently known clinically relevant molecular markers within IDH-mutant astrocytomas grade 2 to 4. Methods: A literature search was performed in five electronic databases for English original papers on patient outcome with respect to a molecular marker as determined by DNA/RNA sequencing, micro-arrays, or DNA methylation profiling in IDH-mutant astrocytomas grade 2 to 4. Papers were included if molecular diagnostics were performed on tumour tissue of at least 15 IDH-mutant astrocytoma patients, and if the investigated molecular markers were not limited to the diagnostic markers MGMT, ATRX, TERT, and/or TP53. Results: The literature search identified 4508 unique articles, published between August 2012 and December 2021, of which ultimately 44 articles were included. Numerous molecular markers from these papers were significantly correlated to patient outcome. The associations between patient outcome and non-canonical IDH mutations, PI3K mutations, high expression of MSH2, high expression of RAD18, homozygous deletion of CDKN2A/B, amplification of PDGFRA, copy number neutral loss of chromosomal arm 17p, loss of chromosomal arm 19q, the G-CIMP-low DNA methylation cluster, high total CNV, and high tumour mutation burden were confirmed in multiple studies. Conclusions: Multiple genetic and epigenetic markers are associated with survival in IDH-mutant astrocytoma patients. Commonly affected are the RB signalling pathway, the RTK-PI3K-mTOR signalling pathway, genomic stability markers, and (epigenetic) gene regulation.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Electrical impedance myography (EIM) is a promising biomarker for amyotrophic lateral sclerosis (ALS). A key issue is how best to utilise the complex high dimensional, multi-frequency data output by EIM to fully characterise the progression of disease.Muscle volume conduction properties were obtained from EIM recordings of the tongue across three electrode configurations and 14 input frequencies (76 Hz-625 kHz). Analyses of individual frequencies, averaged EIM spectra and non-negative tensor factorisation were undertaken. Longitudinal data were collected from 28 patients and 17 healthy volunteers at 3-monthly intervals for a maximum of 9 months. EIM was evaluated against the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) bulbar sub-score, tongue strength and an overall bulbar disease burden score.Longitudinal changes to individual patient EIM spectra demonstrated complex shifts in the spectral shape. At a group level, a clear pattern emerged over time, characterised by an increase in centre frequency and general shift to the right of the spectral shape. Tensor factorisation reduced the spectral data from a total of 168 data points per participant per recording to a single value which captured the complexity of the longitudinal data and which we call tensor EIM (T-EIM). The absolute change in tensor EIM significantly increased within 3 months and continued to do so over the 9-month study duration. In a hypothetical clinical trial scenario tensor EIM required fewer participants (n = 64 at 50% treatment effect), than single frequency measures (n range 87-802) or ALSFRS-R bulbar subscore (n = 298).Changes to tongue EIM spectra over time in ALS are complex. Tensor EIM captured and quantified disease progression and was more sensitive to changes than single frequency EIM measures and other biomarkers of bulbar disease.Objective biomarkers for the assessment of bulbar disease in ALS are lacking. Tensor EIM enhances the biomarker potential of EIM data and can improve bulbar symptom monitoring in clinical trials.

Background Well-being has long been recognized as a key construct in human history. Quantitative studies have been limited in their ability to uncover contextual and cultural nuances that can be leveraged to inform the promotion of well-being. The present study employed a qualitative approach informed by narrative inquiry to understand how individuals in a rapidly developing Asian country experience what it means to be well and what contributes to or detracts from their well-being. Methods A purposeful sample of 50 Thai adults living in Bangkok shared their personal stories of times when they experienced high and low levels of well-being. Data were inductively coded and analysed to identify key domains of participants’ well-being and their inter-connections. Results The results reflect three layers of well-being. Social relationships (i.e., family, friends and acquaintances, and relationships at work or education) are at the center of well-being in Thailand, connecting and supporting a second layer of eight constituent domains of well-being (experience of emotions, sense of self, finances, self-care, demands and responsibilities, thoughts and feelings about the future, personal health, spirituality). The third layer is composed of the societal and physical contexts that are formative for well-being. Conclusions Our findings suggest both universal and culturally unique components of well-being among Thai adults. Implications for the promotion of well-being in Thailand are discussed.

Silicon sensors date back to before 1960 with early Hall and piezoresistive devices. These used simple processing that was part of the early integrated circuit (IC) industry. As the IC industry developed, silicon sensors could benefit from the technological advances. As silicon sensors advanced, there came the need for new technologies specifically for microsystems. This led to a range of 3-D structures using micromachining and enabled the development of both sensors and actuators. The integration of sensors with electronics on a single chip also presented new challenges to ensure that both sensor and electronics would function correctly at the end of the processing. In recent years many new technologies and new materials were introduced to enhance the functionality of microsystems. Some sensors are still based on silicon, but others introduce new materials such as carbon nanotubes and graphene. Technologies that have been used in other applications for many years are now integral part of the microsystem technology portfolio. These include screen printing and inkjet printing. Moving more into the third dimension, 3-D printing presents many new opportunities to fabricate novel structures on a silicon substrate. This tutorial focuses on the additional technologies which have been developed to supplement standard IC processes to create MEMS structures.

Predation is ubiquitous on coral reefs. Among the most charismatic group of reef predators are the top predatory fishes, including sharks and large-bodied bony fishes. Despite the threat presented by top predators, data describing their realized effects on reef community structure and functioning are challenging to produce. Many innovative studies have capitalized on natural experimental conditions to explore predator effects on reefs. Gradients in predator density have been created by spatial patterning of fisheries management. Evidence of prey release has been observed across some reefs, namely that potential prey increase in density when predator density is reduced. While such studies search for evidence of prey release among broad groups or guilds of potential prey, a subset of studies have sought evidence of release at finer population levels. We find that some groups of fishes are particularly vulnerable to the effects of predators and more able to capitalize demographically when predator density is reduced. For example, territorial damselfish appear to realize reliable population expansion with the reduction in predator density, likely because their aggressive, defensive behavior makes them distinctly vulnerable to predation. Relatedly, individual fishes that suffer from debilitating conditions, such as heavy parasite loads, appear to realize relatively stronger levels of prey release with reduced predator density. Studying the effects of predators on coral reefs remains a timely pursuit, and we argue that efforts to focus on the specifics of vulnerability to predation among potential prey and other context-specific dimensions of mortality hold promise to expand our knowledge.

Fluorescent patterns with multiple functions enable high-security anti-counterfeiting labels. Complex material synthesis and patterning processes limit the application of multifunctional fluorescent patterns, so the technology of in situ fluorescent patterning with tunable multimodal capabilities is becoming more necessary. In this work, an in situ fluorescent patterning technology was developed using laser direct writing on solid cellulose film at ambient conditions without masks. The fluorescent intensity and surface microstructure of the patterns could be adjusted by programmable varying of the laser parameters simultaneously. During laser direct writing, carbon dots are generated in situ in a cellulose ester polymer matrix, which significantly simplifies the fluorescent patterning process and reduces the manufacturing cost. Interestingly, the tunable fluorescent intensity empowers the fabrication of visual stereoscopic fluorescent patterns with excitation dependence, further improving its anti-counterfeiting performance. The obtained fluorescent patterns still show ultrahigh optical properties after being immersed in an acid/base solution (pH 5-12) over one month. In addition, the anti-UV performance of the obtained laser-patterned film with transmittance around 90% is comparable to that of commercial UV-resistant films. This work provided an advanced and feasible approach to fabricating programmable, performance-tunable, subtle fluorescent patterns in large-scale for industrial application.

A 4-y-old, spayed female, mixed-breed domesticated rabbit ( Oryctolagus cuniculus domesticus) was presented because of progressive bilateral exophthalmos, with a large mediastinal mass in the cranial thorax. Palliative radiation therapy was elected, and 4 fractions of 5 Gy were delivered twice weekly under general anesthesia using 3-dimensional conformal radiation therapy for a total dose of 20 Gy, guided by an on-board cone beam CT scan. Quality-of-life and respiratory rate improved before sudden death that followed an episode of dyspnea. The overall survival time following initial diagnosis was 93 d, with 68 d after the first dose of radiation. An autopsy was performed, and the mass was diagnosed as a type A thymoma. The diagnosis was confirmed with positive immunohistochemical labeling of the neoplastic cells for cytokeratin 5/6 and cytokeratin 7.

Patellar instability is a broad term that encompasses patellar dislocation, patellar subluxation, and patellar instability. Although both functional and anatomic considerations contribute to symptoms of patellar instability, the most important are thought to be patella alta, trochlear dysplasia, and lateralization of the tibial tubercle. In patients with a history suspicious for prior patellar dislocation, careful evaluation of MRI and radiographic studies can reveal characteristic findings. The most common methods to address patellofemoral instability are medial patellofemoral ligament reconstruction and tibial tubercle osteotomy with either anteromedialization or medialization. Less commonly trochleoplasty is indicated as well. Patients may be treated with one of or a combination of these techniques, each of which has specific indications and complications.

Contains fulltext : 238998.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pancreatic duct disruption or disconnection is a potentially severe complication of necrotizing pancreatitis. With no existing treatment guidelines, it is unclear whether there is any consensus among experts in clinical practice. We evaluated current expert opinion regarding the diagnosis and treatment of pancreatic duct disruption and disconnection in an international case vignette study. METHODS: An online case vignette survey was sent to 110 international expert pancreatologists. Expert selection was based on publications in the last 5 years and/or participation in development of IAP/APA and ESGE guidelines on acute pancreatitis. Consensus was defined as agreement by at least 75% of the experts. RESULTS: The response rate was 51% (n = 56). Forty-four experts (79%) obtained a MRI/MRCP and 52 experts (93%) measured amylase levels in percutaneous drain fluid to evaluate pancreatic duct integrity. The majority of experts favored endoscopic transluminal drainage for infected (peri)pancreatic necrosis and pancreatic duct disruption (84%, n = 45) or disconnection (88%, n = 43). Consensus was lacking regarding the treatment of patients with persistent percutaneous drain production, and with persistent sterile necrosis. CONCLUSION: This international survey of experts demonstrates that there are many areas for which no consensus existed, providing clear focus for future investigation.

Unlike other sarcoma subtypes, myxoid liposarcoma (MLS) has a propensity for extra-pulmonary metastases. Computed tomography (CT) scan of the chest, abdomen, and pelvis has become an accepted practice for surveillance. However, recent literature suggests that this may be inadequate. This study aimed to assess the ability of current imaging methods to detect metastases adequately in this population. The study identified 169 patients with MLS diagnosed between 2000 and 2016. The timing and location of metastases, the reasons leading to the MLS diagnosis, and the imaging methods were recorded. The locations of metastases were classified into the following categories: pulmonary, soft tissue, bone, retroperitoneal, intraperitoneal, solid organ, and lymph node. An initial diagnosis of metastasis was made at presentation with staging CT scan for 3 (10 %) of 31 patients, with a follow-up surveillance CT scan for 15 (48 %) of the patients or with subsequent imaging obtained in response to patient-reported symptoms for 13 (42 %) of the patients. The proportions of patients who had metastases in each location were as follows: soft tissue (84 %), pulmonary (68 %), intraabdominal (48 %), solid organ (48 %), bone (45 %), lymph node (32 %), and retroperitoneal (29 %). Although 14 patients had bone metastases, only 1 patient had a sclerotic/blastic presentation visualized on CT scan, and the diagnosis for the remaining 13 patients was determined by magnetic resonance imaging (MRI). Due to metastatic disease identified outside surveillance imaging for 58 % of the patients, the diversity of locations, and the significant failure of CT and bone scan to identify bone metastases, this study questioned the adequacy of CT scan for surveillance of MLS. Consideration should be given to the use of whole-body MRI for detection of metastasis in MLS.

Our understanding of the unification of jetted AGN has evolved greatly as jet samples have increased in size. Here, based on the largest-ever sample of over 2000 well-sampled jet spectral energy distributions, we examine the synchrotron peak frequency -- peak luminosity plane, and find little evidence for the anti-correlation known as the blazar sequence. Instead, we find strong evidence for a dichotomy in jets, between those associated with efficient or `quasar-mode' accretion (strong/type II jets) and those associated with inefficient accretion (weak/type I jets). Type II jets include those hosted by high-excitation radio galaxies, flat-spectrum radio quasars (FSRQ), and most low-frequency-peaked BL Lac objects. Type I jets include those hosted by low-excitation radio galaxies and blazars with synchrotron peak frequency above 10^15 Hz (nearly all BL Lac objects). We have derived estimates of the total jet power for over 1000 of our sources from low-frequency radio observations, and find that the jet dichotomy does not correspond to a division in jet power. Rather, type II jets are produced at all observed jet powers, down to the lowest levels in our sample, while type I jets range from very low to moderately high jet powers, with a clear upper bound at ~10^43 erg/s The range of jet power in each class matches exactly what is expected for efficient (i.e., a few to 100% Eddington) or inefficient (, Accepted for publication in MNRAS (19 April 2021)

Background Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/− concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization. Results Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.

Purpose This study developed methods to quantify and improve the accuracy of dual-energy CT (DECT)-based bone marrow edema imaging using a clinical CT system. Objectives were: (a) to quantitatively compare DECT with gold-standard, fluid-sensitive MRI for imaging of edema-like marrow signal intensity (EMSI) and (b) to identify image analysis parameters that improve delineation of EMSI associated with acute knee injury on DECT images. Methods DECT images from ten participants with acute knee injury were decomposed into estimated fractions of bone, healthy marrow, and edema based on energy-dependent differences in tissue attenuation. Fluid-sensitive MR images were registered to DECT for quantitative, voxel-by-voxel comparison between the two modalities. An optimization scheme was developed to find attenuation coefficients for healthy marrow and edema that improved EMSI delineation, compared to MRI. DECT method accuracy was evaluated by measuring dice coefficients, mutual information, and normalized cross correlation between the DECT result and registered MRI. Results When applying the optimized three-material decomposition method, dice coefficients for EMSI identified through DECT vs MRI were 0.32 at the tibia and 0.13 at the femur. Optimization of attenuation coefficients improved dice coefficient, mutual information, and cross-correlation between DECT and gold-standard MRI by 48%-107% compared to three-material decomposition using non-optimized parameters, and improved mutual information and cross-correlation by 39%-58% compared to the manufacturer-provided two-material decomposition. Conclusions This study quantitatively evaluated the performance of DECT in imaging knee injury-associated EMSI and identified a method to optimize DECT-based visualization of complex tissues (marrow and edema) whose attenuation parameters cannot be easily characterized. Further studies are needed to improve DECT-based EMSI imaging at the femur.

Fragile X syndrome (FXS), the most prevalent genetic form of intellectual disability, is characterized by intellectual impairment, impaired sociability, aggression, self-injury, hyperactivity, and attention deficits. A consequence of the hyperactivity and attention deficits is that individuals with FXS are frequently diagnosed with attention deficit hyperactivity disorder (ADHD) and treated with medications approved for ADHD (e.g., the α2-agonist clonidine). The pharmacotherapy of FXS is often accompanied with behavioral therapies that rely on positive reinforcement and other operant principles. Despite the commonplace mixture of drug and behavioral therapy, little attention has been paid to the observation that clonidine or other psychotropic drugs may alter operant processes. In the present progressive ratio study, we used a knockout mouse model to test the effects of the fragile X genotype, the α2-agonist clonidine, and the fragile X genotype and clonidine together on operant processes in a positive reinforcement task. We found that clonidine decreased the progressive ratio breakpoint, increased the length of post-reinforcement pauses, and slowed the run rate. None of these effects varied by genotype. The effect on breakpoint suggests that clonidine alters motivation, but analysis using mathematical principles of reinforcement (MPR) did not rule out motor parameters as a contributor. Our findings show that clonidine alters operant behavior and serve as a caution for combining clonidine with behavioral therapies that rely on positive reinforcement. Further research using different murine behaviors (e.g., touchscreen tasks) or different animal models (e.g., knockout rats) is needed to explore the interaction between pharmaco- and behavioral therapy.

Chemical reaction kinetics enable predictive scaling studies and process sensitivity analyses that can substantially accelerate commercial deployment of new catalytic transformation technologies. The absence of suitable kinetic parameters for catalytic fast pyrolysis (CFP) of biomass feedstocks has precluded such de-risking simulation activities. In this work we consider ex situ CFP using a Pt/TiO2 catalyst in a packed bed vapor phase upgrading reactor (VPU) with co-fed H2. We develop a multiscale simulation framework to de-couple apparent kinetics from both intraparticle and reactor-scale transport phenomena. The transport model is integrated with a kinetic scheme that predicts (1) lumped yields of product partially deoxygenated compounds, hydrocarbons, light gases, water, and coke, as well as (2) active site concentration and deactivation of the catalyst. We employ recent advancements in mathematical treatments of cascading reaction systems in the context of an axial-dispersion packed bed reactor model to achieve a rapidly-solving simulation framework that is amenable to iterative regression for kinetic parameter extraction. Results demonstrate accurate predictions of CFP yields within 5% for a variety of conditions, including different reaction times, Pt loadings, and variations in feedstock attributes.

Objectives Modeling the health and care trajectories of lesbian, gay, and bisexual (LGB) is essential to identify inequalities and support needs, yet because of the small sample of LGB people in any one survey, current evidence relies on studies that have poor generalizability and low power. This study assesses the magnitude of health inequalities among older LGB people across 10 outcomes, informed by evidence on the health trajectories and distinct LGB history of the United Kingdom. Method A systematic review was conducted of representative data sources on older LGB and heterosexual people’s health and care status in the United Kingdom. Individual Participant Data (IPD) meta-analysis was employed to synthesize data from up to 25 different sources. To account for the intricacies of individual data sets, the analysis employed a two-stage approach where an odds ratio and standard error was calculated for each data set individually, before being meta-analyzed through DerSimonian and Laird random effects models. Results Among men aged 50+, being gay, bisexual, or having another nonheterosexual orientation is associated with an increased risk of reporting long-term illness and health-related limitations. Indicators of mental health also suggest that gay and bisexual men are more likely to report low life satisfaction and to have attempted suicide over their life time. Among women, differences are apparent with regards to self-rated health as well as with engagement with risky health behaviors. Discussion The findings corroborate the minority stress theory, but they also generate new questions for researchers around when and how these inequalities emerge.

In cases where we can achieve integrated sensors using only layers already in the standard IC layers, the only compatibility issues may be the requirement for additional etch steps. In cases where additional layers are required, either for sensing or protection, we have to consider the compatibility of the materials. These issues can be thermal budget during processing, mechanical stress or chemical contamination. In some cases, this led to the option of hybrid, where the sensor and electronics are on separate chips, but combined in a single package. This paper will examine the development of integrated sensors, and the issues combining additional layers with a standard IC process.

Aim Identification of the processes that generate and maintain species diversity within the same region can provide insight into biogeographic patterns at broader spatiotemporal scales. Hawkfishes in the genus Paracirrhites are a unique taxon to explore with respect to niche differentiation, exhibiting diagnostic differences in coloration, and an apparent center of distribution outside of the Indo–Malay–Philippine (IMP) biodiversity hotspot for coral reef fishes. Our aim is to use next‐generation sequencing methods to leverage samples of a taxon at their center of maximum diversity to explore phylogenetic relationships and a possible mechanism of coexistence. Location Flint Island, Southern Line Islands, Republic of Kiribati. Methods A comprehensive review of museum records, the primary literature, and unpublished field survey records was undertaken to determine ranges for four “arc‐eye” hawkfish species in the Paracirrhites species complex and a potential hybrid. Fish from four Paracirrhites species were collected from Flint Island in the Southern Line Islands, Republic of Kiribati. Hindgut contents were sequenced, and subsequent metagenomic analyses were used to assess the phylogenetic relatedness of the host fish, the microbiome community structure, and prey remains for each species. Results Phylogenetic analyses conducted with recovered mitochondrial genomes revealed clustering of P. bicolor with P. arcatus and P. xanthus with P. nisus, which were unexpected on the basis of previous morphological work in this species complex. Differences in taxonomic composition of gut microbial communities and presumed prey remains indicate likely separation of foraging niches. Main Conclusions Our findings point toward previously unidentified relationships in this cryptic species complex at its proposed center of distribution. The three species endemic to the Polynesian province (P. nisus, P. xanthus, and P. bicolor) cluster separately from the more broadly distributed P. arcatus on the basis of relative abundance of metazoan sequences in the gut (presumed prey remains). Discordance between gut microbial communities and phylogeny of the host fish further reinforce the hypothesis of niche separation., Identification of the processes that generate and maintain species diversity within the same region can provide insight into biogeographic patterns at broader spatiotemporal scales. Here, we use next‐generation sequencing methods to leverage collections of coral reef fish species in the Paracirrhites genus to explore phylogenetic relationships and a possible mechanism of coexistence. Our findings point toward previously unidentified relationships in this cryptic species complex at its proposed center of distribution, and likely trophic partitioning on the basis of gut microbial communities and sequenced prey remains.

Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analysis. A total of 613 and 571 distinct expressed microRNAs were identified in the normal and tumor tissue datasets, respectively (overlap: 480). Among these, 79 (13%) normal tissue microRNAs demonstrated significant cis-heritability (median cis-h2 = 0.15, range: 0.03–0.79) for model training. Similar results were obtained from TCGA tumor samples, with 48 (9%) microRNA expression models successfully trained (median cis-h2 = 0.14, range: 0.06–0.60). Using normal tissue models, we identified two significant TWAS microRNA associations with PrCa risk: over-expression of mir-941 family microRNAs (PTWAS = 2.9E-04) and reduced expression of miR-3617-5p (PTWAS = 1.0E-03). The TCGA tumor TWAS also identified a significant association with miR-941 overexpression (PTWAS = 9.7E-04). Subsequent finemapping of the TWAS results using a multi-tissue database indicated limited evidence of causal status for each microRNA with PrCa risk (posterior inclusion probabilities

A better understanding of transcriptional evolution of IDH-wild-type glioblastoma may be crucial for treatment optimization. Here, we perform RNA sequencing (RNA-seq) (n = 322 test, n = 245 validation) on paired primary-recurrent glioblastoma resections of patients treated with the current standard of care. Transcriptional subtypes form an interconnected continuum in a two-dimensional space. Recurrent tumors show preferential mesenchymal progression. Over time, hallmark glioblastoma genes are not significantly altered. Instead, tumor purity decreases over time and is accompanied by co-increases in neuron and oligodendrocyte marker genes and, independently, tumor-associated macrophages. A decrease is observed in endothelial marker genes. These composition changes are confirmed by single-cell RNA-seq and immunohistochemistry. An extracellular matrix-associated gene set increases at recurrence and bulk, single-cell RNA, and immunohistochemistry indicate it is expressed mainly by pericytes. This signature is associated with significantly worse survival at recurrence. Our data demonstrate that glioblastomas evolve mainly by microenvironment (re-)organization rather than molecular evolution of tumor cells.

Implementing parts per billion-level nitric oxide (NO) sensing at room temperature (RT) is still in extreme demand for monitoring inflammatory respiratory diseases. Herein, we have prepared a kind of core-shell structural Hemin-based nanospheres (Abbr.: Hemin-nanospheres, defined as HNSs) with the core of amorphous Hemin and the shell of acetone-derived carbonized polymer, whose core-shell structure was verified by XPS with argon-ion etching. Then, the HNS-assembled reduced graphene oxide composite (defined as HNS-rGO) was prepared for RT NO sensing. The acetone-derived carbonized polymer shell not only assists the formation of amorphous Hemin core by disrupting their crystallization to release more Fe-N4 active sites, but provides protection to the core. Owing to the unique core-shell structure, the obtained HNS-rGO based sensor exhibited superior RT gas sensing properties toward NO, including a relatively higher response (Ra/Rg = 5.8, 20 ppm), a lower practical limit of detection (100 ppb), relatively reliable repeatability (over 6 cycles), excellent selectivity, and much higher long-term stability (less than a 5% decrease over 120 days). The sensing mechanism has also been proposed based on charge transfer theory. The superior gas sensing properties of HNS-rGO are ascribed to the more Fe-N4 active sites available under the amorphous state of the Hemin core and to the physical protection by the shell of acetone-derived carbonized polymer. This work presents a facile strategy of constructing a high-performance carbon-based core-shell nanostructure for gas sensing.

Secondary bacterial infection is a common complication in severe influenza virus infections. During the H1N1 pandemic of 2009, increased mortality was observed among healthy young adults due to secondary bacterial pneumonia, one of the most frequent bacterial species being Streptococcus pneumoniae (Spn). Previous studies in mice and ferrets have suggested a synergistic relationship between Spn and influenza viruses. In this study, the ferret model was used to examine whether secondary Spn infection (strains BHN97 and D39) influence replication and airborne transmission of the 2009 pandemic H1N1 virus (H1N1pdm09). Secondary infection with Spn after H1N1pdm09 infection consistently resulted in a significant decrease in viral titers in the ferret nasal washes. While secondary Spn infection appeared to negatively impact influenza virus replication, animals precolonized with Spn were equally susceptible to H1N1pdm09 airborne transmission. In line with previous work, ferrets with preceding H1N1pdm09 and secondary Spn infection had increased bacterial loads and more severe clinical symptoms as compared to animals infected with H1N1pdm09 or Spn alone. Interestingly, the donor animals that displayed the most severe clinical symptoms had reduced airborne transmission of H1N1pdm09. Based on these data, we propose an asymmetrical relationship between these two pathogens, rather than a synergistic one, since secondary bacterial infection enhances Spn colonization and pathogenesis but decreases viral titers.

The challenge in establishing an early-sown wheat crop in southern Australia is the need for consistently high seedling emergence when sowing deep in subsoil moisture (>10 cm) or into dry top-soil (4 cm). However, the latter is strongly reliant on a minimum soil water availability to ensure successful seedling emergence. This study aimed to: (1) evaluate 233 Australian and selected international wheat genotypes for consistently high seedling emergence under limited soil water availability when sown in 4 cm of top-soil in field and glasshouse (GH) studies; (2) ascertain genetic loci associated with phenotypic variation using a genome-wide association study (GWAS); and (3) compare across loci for traits controlling coleoptile characteristics, germination, dormancy, and pre-harvest sprouting. Despite significant (P < 0.001) environment and genotype-by-environment interactions within and between field and GH experiments, eight genotypes that included five cultivars, two landraces, and one inbred line had consistently high seedling emergence (mean value > 85%) across nine environments. Moreover, 21 environment-specific quantitative trait loci (QTL) were detected in GWAS analysis on chromosomes 1B, 1D, 2B, 3A, 3B, 4A, 4B, 5B, 5D, and 7D, indicating complex genetic inheritance controlling seedling emergence. We aligned QTL for known traits and individual genes onto the reference genome of wheat and identified 16 QTL for seedling emergence in linkage disequilibrium with coleoptile length, width, and cross-sectional area, pre-harvest sprouting and dormancy, germination, seed longevity, and anthocyanin development. Therefore, it appears that seedling emergence is controlled by multifaceted networks of interrelated genes and traits regulated by different environmental cues.

We introduce the AusTraits database - a compilation of values of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 448 traits across 28,640 taxa from field campaigns, published literature, taxonomic monographs, and individual taxon descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological attributes (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual- and species-level measurements coupled to, where available, contextual information on site properties and experimental conditions. This article provides information on version 3.0.2 of AusTraits which contains data for 997,808 trait-by-taxon combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data, which also provides a template for other national or regional initiatives globally to fill persistent gaps in trait knowledge., Measurement(s)plant traitTechnology Type(s)digital curationSample Characteristic - OrganismViridiplantaeSample Characteristic - LocationAustralia Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14545755

Here we study emulsification in a model experimental system comprised of water, an oil and colloidal particles. The particles are charge-stabilised colloidal silica; unsurprisingly, by varying the concentration of salt the degree of flocculation of the particles can be modified. The influence of salt on the formation of particle-stabilised oil droplets goes well beyond considerations of the colloidal stability of the particles. Our results demonstrate that the influence of salt on the particle–particle interaction is less important for emulsion formation than the influence of salt on both the particle wettability and the particle–interface interaction.

Background The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) has recommended that isocitrate dehydrogenase 1 and 2 wildtype (IDH1/2wt) diffuse lower-grade gliomas (LGGs) World Health Organization (WHO) grade II or III that present with (i) a telomerase reverse transcriptase promoter mutation (pTERTmt), and/or (ii) gain of chromosome 7 combined with loss of chromosome 10, and/or (iii) epidermal growth factor receptor (EGFR) amplification should be reclassified as diffuse astrocytic glioma, IDH1/2 wildtype, with molecular features of glioblastoma, WHO grade IV (IDH1/2wt astrocytomas WHO IV). This paper describes the overall survival (OS) of IDH1/2wt astrocytoma WHO IV patients, and more in detail patients with tumors with pTERTmt only. Methods In this retrospective multicenter study, we compared the OS of 71 IDH1/2wt astrocytomas WHO IV patients, with radiological characteristics of LGGs, with the OS of 197 IDH1/2wt glioblastoma patients. Moreover, we compared the OS of 22 pTERTmt only astrocytoma patients with the OS of the IDH1/2wt glioblastoma patients. Results Median OS was similar for IDH1/2wt astrocytoma WHO IV patients (23.8 mo) and IDH1/2wt glioblastoma patients (19.2 mo) (Cox proportional hazards model: hazard ratio [HR] 1.27, 95% CI: 0.85–1.88, P = 0.242). OS was also similar in patients with IDH1/2wt astrocytomas WHO IV, pTERTmt only, and IDH1/2wt glioblastomas (HR 1.15, 95% CI: 0.64–2.10, P = 0.641). Conclusions The presented data confirm the cIMPACT-NOW recommendation and we propose that IDH1/2wt astrocytomas WHO IV in the absence of other qualifying mutations should be classified as IDH1/2wt glioblastomas.

The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is orchestrated to maintain long-range gene expression is poorly understood. Here we perform RNAi knockdown to reduce CTCF levels and reveal a shared subset of CTCF-bound sites are robustly resistant to protein depletion. The ‘persistent’ CTCF sites are enriched at domain boundaries and chromatin loops constitutive to all cell types. CRISPR-Cas9 deletion of 2 persistent CTCF sites at the boundary between a long-range epigenetically active (LREA) and silenced (LRES) region, within the Kallikrein (KLK) locus, results in concordant activation of all 8 KLK genes within the LRES region. CTCF genome-wide depletion results in alteration in Topologically Associating Domain (TAD) structure, including the merging of TADs, whereas TAD boundaries are not altered where persistent sites are maintained. We propose that the subset of essential CTCF sites are involved in cell-type constitutive, higher order chromatin architecture., The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is regulated remains poorly understood. Here the authors find that there is a shared subset of CTCF-bound sites resistant to protein depletion in different cell lines, which are enriched at domain boundaries and chromatin loops constitutive to all cell types.