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Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (nobserved= 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.

Le public est de plus en plus sensible a l'importance de divulguer et de gerer les conflits d'interets (CI) lies a l'elaboration des guides de pratique clinique et des directives [...]

Public awareness regarding the importance of disclosing and managing conflicts of interest (COIs) during the development of clinical practice and public health guidelines is growing, owing to recent high-profile news [...]

BACKGROUND: Guideline recommendations may be affected by flaws in the process, inappropriate panel member selection or conduct, conflicts of interest and other factors. To our knowledge, no validated tool exists to evaluate guideline development from the perspective of those directly involved in the process. Our objective was to develop and validate a universal tool, the PANELVIEW instrument, to assess guideline processes, methods and outcomes from the perspective of the participating guideline panellists and group members. METHODS: We performed a systematic literature search and surveys of guideline groups (identified through contacting international organizations and convenience sampling of working panels) to inform item generation. Subsequent groups of guideline methodologists and panellists reviewed items for face validity and missing items. We used surveys, interviews and expert review for item reduction and phrasing. For reliability assessment and feedback, we tested the PANELVIEW tool in 8 international guideline groups. RESULTS: We surveyed 62 members from 13 guideline panels, contacted 19 organizations and reviewed 20 source documents to generate items. Fifty-three additional key informants provided feedback about phrasing of the items and response options. We reduced the number of items from 95 to 34 across domains that included administration, training, conflict of interest, group dynamics, chairing, evidence synthesis, formulating recommendations and publication. The tool takes about 10 minutes to complete and showed acceptable measurement properties. INTERPRETATION: The PANELVIEW instrument fills a gap by enabling guideline organizations to involve clinicians, patients and other participants in evaluating their guideline processes. The tool can inform quality improvement of existing or new guideline programs, focusing on insight into and transparency of the guideline development process, methods and outcomes., As a product of a group process that involves project planning, synthesizing evidence and deliberation by guideline group members to reach consensus and formulate recommendations, health guidelines are highly influential [...]

The burden of chronic kidney disease and associated risk of kidney failure are increasing in Africa. The management of people with chronic kidney disease is fraught with numerous challenges because of limitations in health systems and infrastructures for care delivery. From the third iteration of the International Society of Nephrology Global Kidney Health Atlas, we describe the status of kidney care in the ISN Africa region using the World Health Organization building blocks for health systems. We identified limited government health spending, which in turn led to increased out-of-pocket costs for people with kidney disease at the point of service delivery. The health care workforce across Africa was suboptimal and further challenged by the exodus of trained health care workers out of the continent. Medical products, technologies, and services for the management of people with nondialysis chronic kidney disease and for kidney replacement therapy were scarce due to limitations in health infrastructure, which was inequitably distributed. There were few kidney registries and advocacy groups championing kidney disease management in Africa compared with the rest of the world. Strategies for ensuring improved kidney care in Africa include focusing on chronic kidney disease prevention and early detection, improving the effectiveness of the available health care workforce (e.g., multidisciplinary teams, task substitution, and telemedicine), augmenting kidney care financing, providing quality, up-to-date health information data, and improving the accessibility, affordability, and delivery of quality treatment (kidney replacement therapy or conservative kidney management) for all people living with kidney failure.

Pseudomonasspp. causes significant losses in aquaculture, consecutive use of antibiotics, and reveals bacterial resistance; therefore, therapeutic bacteriophages, commonly called phages, are a promising potential alternative to antibiotics in the management of bacterial infections of a wide range of organisms, including cultured fish. The novelty of current work is represented in examining the lytic activity of four phages and their combination compared to the antibiotic streptomycin on Pseudomonas aeruginosa-infected Nile tilapia (Oreochromis niloticus) while measuring the hematological and blood biochemical parameters as a response for phage therapy. This study evaluated the in vitrokilling curve for each phage using a growth curve that measured the OD600after a single phage suspension was combined with the host P. aeruginosa, considered the best multiplicity of infection (MOI) for each phage. A144 healthy fish were acclimatized in the laboratory and divided into six groups: control, P. aeruginosa-infected fish, streptomycin, phage Ps1, Ps2, both (Ps1 and Ps2), were added to the T3, T4, T5, and T6 groups, respectively. Our findings demonstrated that P. aeruginosainfection caused surface body hemorrhages, tail and fin rot, irritated skin, superficial ulcers, and 100% mortality through 14 days. P. aeruginosacaused a reduction in hemoglobin (Hb), red blood cells (RBCs), platelet number (PLt), and platelet crit (PCT) count, protein, albumin, and A/G ratio; however, an increase in hematocrit (Hct), red cell distribution width (RDW), PDW, MPV compared to other groups after three days of infection and the effects increased after 12 days post-infection. The fish vaccinated with P1 (T4) and P1+P2 (T6) showed enhanced levels of Hb, RBCs, PLt, PCt, protein, albumin and decreased levels of RDW, PDW, MPV, and liver and kidney enzymes with enhanced contents more than streptomycin and closer to the control group. The biochemical markers recorded significant changes indicating liver and kidney impairments due to the infection with P. aeruginosa. It can be concluded that P1 and P1+P2 combinations could be used as therapy in Pseudomonas-infected fish to enhance their blood parameters and performance.

Cell–cell interactions are essential for the function and contextual regulation of biological tissues. We present a platform for high-throughput microfluidics-supported genetic screening of functional regulators of cell–cell interactions. Systematic perturbation of encapsulated associated cells followed by sequencing (SPEAC-seq) combines genome-wide CRISPR libraries, cell coculture in droplets and microfluidic droplet sorting based on functional read-outs determined by fluorescent reporter circuits to enable the unbiased discovery of interaction regulators. This technique overcomes limitations of traditional methods for characterization of cell–cell communication, which require a priori knowledge of cellular interactions, are highly engineered and lack functional read-outs. As an example of this technique, we describe the investigation of neuroinflammatory intercellular communication between microglia and astrocytes, using genome-wide CRISPR–Cas9 inactivation libraries and fluorescent reporters of NF-κB activation. This approach enabled the discovery of thousands of microglial regulators of astrocyte NF-κB activation important for the control of central nervous system inflammation. Importantly, SPEAC-seq can be adapted to different cell types, screening modalities, cell functions and physiological contexts, only limited by the ability to fluorescently report cell functions and by droplet cultivation conditions. Performing genome-wide screening takes less than 2 weeks and requires microfluidics capabilities. Thus, SPEAC-seq enables the large-scale investigation of cell–cell interactions.

Metal recycling in scrapyards, where workers cut decommissioned structures using gas torches, is labor-intensive, difficult, and dangerous. As global metal scrap recycling demands are rising, robotics and automation technologies could play a significant role to address this demand. However, the unstructured nature of the scrap cutting problem—due to highly variable object shapes and environments—poses significant challenges to integrate robotic solutions. We propose a novel collaborative workflow for robotic metal cutting that combines worker expertise with robot autonomy. In this workflow, the skilled worker studies the scene, determines an appropriate cutting reference, and marks it on the object with spray paint. The robot, then, autonomously explores the surface of the object for identifying and reconstructing the drawn reference, converts it to a cutting trajectory, and finally executes the cut. This paper focuses on the surface exploration and cutting reference reconstruction tasks, which require appropriate next view planning (NVP) algorithms. We devise three NVP algorithms enabling the robot to explore and extract desired features from the scene, i.e., the drawn reference, without requiring any a priori object model. Contrasting with global or feature-agnostic NVP algorithms, our approaches guide the robot via desired local features to increase the efficiency of the exploration. We evaluate our NVP algorithms against six categories of objects both in simulation and in physical experiments. Note to Practitioners—This work is motivated by the need of extracting a desired cutting reference determined and drawn on the object by scrap yard workers. From the robot’s perspective, it must explore and reconstruct the drawing, starting from an unknown scene containing an unknown object featuring an unknown drawing. We assume that an RGB-D camera is attached to the tool-tip of the robot, and the color of the drawn path is significantly different from the object’s color. The goal of the robotic system is to explore the object surface to uncover the drawn path entirely without colliding with the object. The exploration algorithm must overcome complex object shapes and must be fast enough for practical use in scrap yards. This means conventional exploration (active vision) techniques are insufficient since they focus on exploring the entirety of the object, which is unnecessary for our task and is time-consuming. Our methods exploit the drawing information to guide the exploration for quickly determining a suitable viewpoint, which results in an efficient extraction of the entire cutting reference, without needing to explore the entire object’s surface. Our algorithms are robust against adversarial features such as discontinuous, non-smooth, or self-occluded object surfaces. Our feature-driven strategies are not limited to robotic scrap cutting as they are applicable to any viewpoint planning problem requiring high performance while extracting the local features in the scene.

The intensive and repeated use of chemical herbicides has led to the emergence of herbicide-resistant weeds, which, in addition to their environmental impacts, also pose significant threats to human and animal health. This study aimed to explore the potential of oilseed industrial wastes, specifically soybean and flaxseed meals, as safe and environmentally friendly bioherbicides for controlling weeds associated with onion crops. Two field experiments were conducted along two successive winter of 2020/21 and 2021/22. Treatments involved foliar spray of soybean and flaxseed meals in three different concentrations (15, 30 and 45%), mulching of seed meals, oxyfluorfen herbicide, two hand hoeing and untreated weedy check. The findings demonstrated that all weed control treatments significantly reduced weed density, biomass and nutrient uptake. Two hand hoeing, oxyfluorfen herbicide and the mulching of soybean and flaxseed meals alternated in the top rank for weed control, showing minimal significant differences among them. Following these effective treatments, soybean meal extracts at 45 and 30% exhibited notable weed control compared to the weedy check. The greatest enhancement in onion growth, yield characteristics and bulb quality was observed with the application of hand hoeing, soybean and flaxseed meal mulching treatments, with no significant differences between them. High-Performance Liquid Chromatography (HPLC) fractionation of both meals identified various phenolic acids at different concentrations. Practically, these safe efficient treatments proved progress on chemical herbicide. Hence, onion farmers are advised to apply soybean and flaxseed meals mulching safe treatments as alternative to harmful chemical herbicides under all experimental conditions.

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1–8(EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group. Rapid reviews (RRs) use modified systematic review methods to accelerate the review process while maintaining systematic, transparent and reproducible methods. This paper addresses considerations for rating the certainty of evidence (COE) in RRs. We recommend the full implementation of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) for Cochrane RRs if time and resources allow.If time or other resources do not permit the full implementation of GRADE, the following recommendations can be considered: (1) limit rating COE to the main intervention and comparator and limit the number of outcomes to critical benefits and harms; (2) if a literature review or a Delphi approach to rate the importance of outcomes is not feasible, rely on informal judgements of knowledge users, topic experts or team members; (3) replace independent rating of the COE by two reviewers with single-reviewer rating and verification by a second reviewer and (4) if effect estimates of a well-conducted systematic review are incorporated into an RR, use existing COE grades from such a review. We advise against changing the definition of COE or the domains considered part of the GRADE approach for RRs.

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With advances in genetics, it is tempting to assume that the ‘family history’ of a patient is an imperfect proxy for information we can already glean from genetics and laboratory tests. However, this study shows that much of the information contained in the self-reported family history of heart disease is not captured by currently available genetic and clinical biomarkers and highlights an important knowledge gap. Clinically used biomarkers explained only 21.9% of the likelihood of a patient reporting a family history of heart disease, while genetics explained 22.2%, and a combined model explained 36% of this likelihoodThe majority of the risk of reporting a family history went unexplained, implying that family history still has major relevance in clinical practice.Structured Graphical AbstractPopulation attributable risk percent for family history of heart disease by individual risk factors. Here, we present the population attributable risk for each risk factor, individually modeled for reported family history of heart disease, controlling for age and sex. For all continuous variables, the top four quintiles were compared to the bottom quintile, as indicated by [2nd–5th quintiles vs. 1st quintile (reference)]. A lower bound of 0 was created for PAR.

Chronic noncancer pain includes any painful condition that persists for at least three months and is not associated with malignant disease. (1) According to seven national surveys conducted between 1994 [...]

Byline: Adel. El-Badrawy, Basma. Gadelhak, Eman. Helmy, Omar. Farouk, Tamer. Fady, Basel. Refky, Maha. Elzaafarany, Ziad. Emarah, Mona. Taalab, Noha. Eisa, Shahira. El-Etreby, Monir. Bahgat, Mohammad. El-Badrawy, Hatem. Elalfy, Tarek. [...]

Tumeurs à cellules de Leydig (TCL) sont une entité rare. L’objectif de cette étude est de présenter notre expérience avec leur traitement.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α–NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

Background: Meta-analyses of continuous outcomes typically provide enough information for decision-makers to evaluate the extent to which chance can explain apparent differences between interventions. The interpretation of the magnitude of these differences --from trivial to large--can, however, be challenging. We investigated clinicians' understanding and perceptions of usefulness of 6 statistical formats for presenting continuous outcomes from meta-analyses (standardized mean difference, minimal important difference units, mean difference in natural units, ratio of means, relative risk and risk difference). Methods: We invited 610 staff and trainees in internal medicine and family medicine programs in 8 countries to participate. Paper-based, self-administered questionnaires presented summary estimates of hypothetical interventions versus placebo for chronic pain. The estimates showed either a small or a large effect for each of the 6 statistical formats for presenting continuous outcomes. Questions addressed participants' understanding of the magnitude of treatment effects and their perception of the usefulness of the presentation format. We randomly assigned participants 1 of 4 versions of the questionnaire, each with a different effect size (large or small) and presentation order for the 6 formats (1 to 6, or 6 to 1). Results: Overall, 531 (87.0%) of the clinicians responded. Respondents best understood risk difference, followed by relative risk and ratio of means. Similarly, they perceived the dichotomous presentation of continuous outcomes (relative risk and risk difference) to be most useful. Presenting results as a standardized mean difference, the longest standing and most widely used approach, was poorly understood and perceived as least useful. Interpretation: None of the presentation formats were well understood or perceived as extremely useful. Clinicians best understood the dichotomous presentations of continuous outcomes and perceived them to be the most useful. Further initiatives to help clinicians better grasp the magnitude of the treatment effect are needed., Health professionals increasingly rely on summary estimates from systematic reviews and meta-analyses to guide their clinical decisions and to provide information for shared decision-making. Meta-analyses of clinical trials typically provide [...]

Layer transfer techniques have been extensively explored for semiconductor device fabrication as a path to reduce costs and to form heterogeneously integrated devices. These techniques entail isolating epitaxial layers from an expensive donor wafer to form freestanding membranes. However, current layer transfer processes are still low-throughput and too expensive to be commercially suitable. Here we report a high-throughput layer transfer technique that can produce multiple compound semiconductor membranes from a single wafer. We directly grow two-dimensional (2D) materials on III–N and III–V substrates using epitaxy tools, which enables a scheme comprised of multiple alternating layers of 2D materials and epilayers that can be formed by a single growth run. Each epilayer in the multistack structure is then harvested by layer-by-layer mechanical exfoliation, producing multiple freestanding membranes from a single wafer without involving time-consuming processes such as sacrificial layer etching or wafer polishing. Moreover, atomic-precision exfoliation at the 2D interface allows for the recycling of the wafers for subsequent membrane production, with the potential for greatly reducing the manufacturing cost.

To provide evidence‐based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. Application of these recommendations should consider patients’ individual risk for vaccine‐preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision‐making with patients is encouraged in clinical settings.

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Background: Although several tools to evaluate the credibility of health care guidelines exist, guidance on practical steps for developing guidelines is lacking. We systematically compiled a comprehensive checklist of items linked to relevant resources and tools that guideline developers could consider, without the expectation that every guideline would address each item. Methods: We searched data sources, including manuals of international guideline developers, literature on guidelines for guidelines (with a focus on methodology reports from international and national agencies, and professional societies) and recent articles providing systematic guidance. We reviewed these sources in duplicate, extracted items for the checklist using a sensitive approach and developed overarching topics relevant to guidelines. In an iterative process, we reviewed items for duplication and omissions and involved experts in guideline development for revisions and suggestions for items to be added. Results: We developed a checklist with 18 topics and 146 items and a webpage to facilitate its use by guideline developers. The topics and included items cover all stages of the guideline enterprise, from the planning and formulation of guidelines, to their implementation and evaluation. The final checklist includes links to training materials as well as resources with suggested methodology for applying the items. Interpretation: The checklist will serve as a resource for guideline developers. Consideration of items on the checklist will support the development, implementation and evaluation of guidelines. We will use crowdsourcing to revise the checklist and keep it up to date., Health care guidelines and their appropriate implementation are of interest to national organizations, professional societies, health care providers, policy-makers, patients and the public. Several tools to evaluate the credibility of [...]

Multiple sclerosis is a chronic inflammatory disease of the central nervous system1. Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis2,3. However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes. Here, to address these challenges, we developed focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. We applied FIND-seq to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in multiple sclerosis and experimental autoimmune encephalomyelitis4. Using FIND-seq in combination with conditional-knockout mice, in vivo CRISPR–Cas9-driven genetic perturbation studies and bulk and single-cell RNA sequencing analyses of samples from mouse experimental autoimmune encephalomyelitis and humans with multiple sclerosis, we identified a new role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, we used FIND-seq to identify a therapeutically targetable mechanism that limits XBP1-driven pathogenic astrocyte responses. FIND-seq enables the investigation of previously inaccessible cells, including rare cell subsets defined by unique gene expression signatures or other nucleic acid markers.

Identification of individuals at highest risk of coronary artery disease (CAD)—ideally before onset—remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMultstrongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10–2.19, P< 0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMultwas also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70–1.76, P< 0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMultdemonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMultfor CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.

First, a family of quadratic displacement operators based on group Fourier Transform has been proposed for joint distribution analysis. Second, considering the quadratic displacement operators, a novel millimeter-wave massive MIMO channel tracking has been proposed in Time-Angle (TA) plane. Due to a poor scattering environment, millimeter-wave communication suffers from an ill-conditioned channel matrix. Computationally effective compressed sensing has been proposed to estimate a few dominant paths. These methods rely on orthogonal pilot signals to estimate the channel reliably. However, applying compressed-sensing solutions to the continuous channel leads to significant pilot overhead. To reduce the pilot overhead, one needs to consider the channel dynamics, particularly the spectral overlap between the channel samples. Considering that channel spectral properties can be represented as a joint time-angle distribution, we propose a novel quadratic displacement operator in TA-plane. Considering group Fourier transform in TA-plane, we show that the subderivative of an angular parameter is the dual group of the original angular signal. For a group transform defined over the finite Abelian group, with respect to the finite-dimensional antenna arrays, the purposed time-angle representation matches the cover space of manifold defined in the virtual channel model recommended by A. Sayeed. In TA-plane, the quadratic displacement operator maps old time-angle coordinate onto a new coordinate by taking to account the local spectral properties of the channel samples. By applying the purposed quadratic displacement operator to the Saleh-Valenzuela channel model, the time evolution operator for directional millimeter-wave channel has been derived. Assuming independently identically distributed multipath contribution, we show that channel Wigner distribution is the direct sum of the cluster-wise Wigner distribution. Accordingly, we have shown that the continuous linear time-variant channel transfer function can be represented as the Hadamard product between Wigner distribution of the channel and Saleh-Valenzuela model. Considering the fact that the density matrix is a Weyl correspondence of Wigner distribution, a union of subspaces method has been employed to construct the density matrix for channels samples with slightly different states. Numerical results have been presented to evaluate the performance of the proposed channel tracking method.

An evidence-based approach is considered the gold standard for health decision-making. Sometimes, a guideline panel might judge the certainty that the desirable effects of an intervention clearly outweigh its undesirable effects as high, but the body of supportive evidence is indirect. In such cases, the application of the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach for grading the strength of recommendations is inappropriate. Instead, the GRADE Working Group has recommended developing ungraded best or good practice statement (GPS) and developed guidance under which circumsances they would be appropriate.Through an evaluation of COVID-1- related recommendations on the eCOVID Recommendation Map (COVID-19.recmap.org), we found that recommendations qualifying a GPS were widespread. However, guideline developers failed to label them as GPS or transparently report justifications for their development. We identified ways to improve and facilitate the operationalisation and implementation of the GRADE guidance for GPS.Herein, we propose a structured process for the development of GPSs that includes applying a sequential order for the GRADE guidance for developing GPS. This operationalisation considers relevant evidence-to-decision criteria when assessing the net consequences of implementing the statement, and reporting information supporting judgments for each criterion. We also propose a standardised table to facilitate the identification of GPS and reporting of their development. This operationalised guidance, if endorsed by guideline developers, may palliate some of the shortcomings identified. Our proposal may also inform future updates of the GRADE guidance for GPS.

Living systematic reviews (LSRs) are systematic reviews that are continually updated, incorporating relevant new evidence as it becomes available. LSRs are critical for decision-making in topics where the evidence continues to evolve. It is not feasible to continue to update LSRs indefinitely; however, guidance on when to retire LSRs from the living mode is not clear. We propose triggers for making such a decision. The first trigger is to retire LSRs when the evidence becomes conclusive for the outcomes that are required for decision-making. Conclusiveness of evidence is best determined based on the GRADE certainty of evidence construct, which is more comprehensive than solely relying on statistical considerations. The second trigger to retire LSRs is when the question becomes less pertinent for decision-making as determined by relevant stakeholders, including people affected by the problem, healthcare professionals, policymakers and researchers. LSRs can also be retired from a living mode when new studies are not anticipated to be published on the topic and when resources become unavailable to continue updating. We describe examples of retired LSRs and apply the proposed approach using one LSR about adjuvant tyrosine kinase inhibitors in high-risk renal cell carcinoma that we retired from a living mode and published its last update.

Graphical abstract:

The radioactive and hazardous nature of thorium demands the fabrication of efficient electrodes for its sensitive and selective monitoring in aqueous environments. The present paper reports the construction and characterization of a new carbon paste electrode (CPE) chemically modified by octyl phenyl acid phosphate (OPAP) as a selective recognition agent for the potentiometric assay of thorium(IV) ions. Improved sensitivity, electrical conductivity, and selectivity were achieved by incorporating oxidized multi-walled carbon nanotubes (o-MWCNTs) into the carbon paste composition. The electrochemical performance of the developed electrode was evaluated regarding the paste ingredients, response time, and working pH range. The standard CPE potentials, E°, were determined at various temperatures and the isothermal temperature coefficient was calculated. The optimized CPE showed a Nernstian slope of 14.65 ± 0.38 mV decade−1over the concentration range of 4.82 × 10–7–1.00 × 10–1mol L−1. The electrode possessed a short response time (9 s), independence of the solution pH over the range of 2.5–5.5, and a relatively long operational lifetime (˃ 3 months). The selectivity coefficients indicated the good discrimination ability of the developed CPE towards thorium(IV) ion compared to various common ions. Aiming to judge the practical utility of the developed CPE, it was successfully used for the potentiometric analysis of thorium(IV) ions in various real aqueous matrices with sensible results.

COVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE).These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE.ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment.The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation.This recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

Background: COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. Results: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Conclusions: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1—a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR–NF-κB–C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.

IMPORTANCE: A significant limitation of femoral artery access for cardiac interventions is the increased risk of vascular complications and bleeding compared with radial access. Strategies to make femoral access safer are needed. OBJECTIVE: To determine whether routinely using ultrasonography guidance for femoral arterial access for coronary angiography/intervention reduces bleeding or vascular complications. DESIGN, SETTING, AND PARTICIPANTS: The Routine Ultrasound Guidance for Vascular Access for Cardiac Procedures (UNIVERSAL) randomized clinical trial is a multicenter, prospective, open-label trial of ultrasonography-guided femoral access vs no ultrasonography for coronary angiography or intervention with planned femoral access. Patients were randomized from June 26, 2018, to April 26, 2022. Patients with ST-elevation myocardial infarction were not eligible. INTERVENTIONS: Ultrasonography guidance vs no ultrasonography guidance for femoral arterial access on a background of fluoroscopic landmarking. MAIN OUTCOMES AND MEASURES: The primary composite outcome is the composite of major bleeding based on the Bleeding Academic Research Consortium 2, 3, or 5 criteria or major vascular complications within 30 days. RESULTS: A total of 621 patients were randomized at 2 centers in Canada (mean [SD] age, 71 [10.24] years; 158 [25.4%] female). The primary outcome occurred in 40 of 311 patients (12.9%) in the ultrasonography group vs 50 of 310 patients (16.1%) without ultrasonography (odds ratio, 0.77 [95% CI, 0.49-1.20]; P = .25). The rates of Bleeding Academic Research Consortium 2, 3, or 5 bleeding were 10.0% (31 of 311) vs 10.7% (33 of 310) (odds ratio, 0.93 [95% CI, 0.55-1.56]; P = .78). The rates of major vascular complications were 6.4% (20 of 311) vs 9.4% (29 of 310) (odds ratio, 0.67 [95% CI, 0.37-1.20]; P = .18). Ultrasonography improved first-pass success (277 of 311 [86.6%] vs 222 of 310 [70.0%]; odds ratio, 2.76 [95% CI, 1.85-4.12]; P &lt; .001) and reduced the number of arterial puncture attempts (mean [SD], 1.2 [0.5] vs 1.4 [0.8]; mean difference, −0.26 [95% CI, −0.37 to −0.16]; P &lt; .001) and venipuncture (10 of 311 [3.1%] vs 37 of 310 [11.7%]; odds ratio, 0.24 [95% CI, 0.12-0.50]; P &lt; .001) with similar times to access (mean [SD], 114 [185] vs 129 [206] seconds; mean difference, −15.1 [95% CI, −45.9 to 15.8]; P = .34). All prerandomization prespecified subgroups were consistent with the overall finding. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, use of ultrasonography for femoral access did not reduce bleeding or vascular complications. However, ultrasonography did reduce the risk of venipuncture and number of attempts. Larger trials may be required to demonstrate additional potential benefits of ultrasonography-guided access. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03537118

Europium doped titanium dioxide thin films were synthesized by sol–gel method to enhance the photocatalytic activity and achieve efficient treatment for industrial pharmaceutical effluent, under solar irradiation. Thin films were characterized by X-ray diffraction technique. X-ray diffraction pattern demonstrate that both pure and europium doped titanium dioxide thin films exhibit anatase phase of tetragonal structure. The crystallite size of europium doped titanium dioxide was reduced from 38.40 to 11.32 nm with an increase in europium doping percentage. Also, the thickness of the deposited films was in the range of 33.95–44.21 μm. The reflectance spectra change with dopant and the band gap values were gradually decrease from 3.75 to 3.5 eV with doping concentration increment. Further photocatalytic performances of europium doped titanium dioxide thin films for the remediation of a local industrial effluent were also investigated. The concentration of dopant was varied from 0 to 0.28 mol%. The results showed that 91% of the chemical oxygen demand was reduced. Moreover, the mineralization yield was achieved 95%, with 0.13 mol% of europium doped titanium dioxide, after 6 h under solar irradiation, confirming the efficiency of the europium doped titanium dioxide photocatalytic process.

Heterogeneous integration of single-crystal materials offers great opportunities for advanced device platforms and functional systems1. Although substantial efforts have been made to co-integrate active device layers by heteroepitaxy, the mismatch in lattice polarity and lattice constants has been limiting the quality of the grown materials2. Layer transfer methods as an alternative approach, on the other hand, suffer from the limited availability of transferrable materials and transfer-process-related obstacles3. Here, we introduce graphene nanopatterns as an advanced heterointegration platform that allows the creation of a broad spectrum of freestanding single-crystalline membranes with substantially reduced defects, ranging from non-polar materials to polar materials and from low-bandgap to high-bandgap semiconductors. Additionally, we unveil unique mechanisms to substantially reduce crystallographic defects such as misfit dislocations, threading dislocations and antiphase boundaries in lattice- and polarity-mismatched heteroepitaxial systems, owing to the flexibility and chemical inertness of graphene nanopatterns. More importantly, we develop a comprehensive mechanics theory to precisely guide cracks through the graphene layer, and demonstrate the successful exfoliation of any epitaxial overlayers grown on the graphene nanopatterns. Thus, this approach has the potential to revolutionize the heterogeneous integration of dissimilar materials by widening the choice of materials and offering flexibility in designing heterointegrated systems.

COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE).

COVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE).These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19.ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 as part of the living phase of these guidelines.The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19–related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants.This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19–related acute illness.

Background: Many academic medical centres have introduced strategies to assess the productivity of faculty as part of compensation schemes. We conducted a systematic review of the effects of such strategies on faculty productivity. Methods: We searched the MEDLINE, Healthstar, Embase and PsycInfo databases from their date of inception up to October 2011. We included studies that assessed academic productivity in clinical, research, teaching and administrative activities, as well as compensation, promotion processes and satisfaction. Results: Of 531 full-text articles assessed for eligibility, we included 9 articles reporting on eight studies. The introduction of strategies for assessing academic productivity as part of compensation schemes resulted in increases in clinical productivity (in six of six studies) in terms of clinical revenue, the work component of relative-value units (these units are nonmonetary standard units of measure used to indicate the value of services provided), patient satisfaction and other departmentally used standards. Increases in research productivity were noted (in five of six studies) in terms of funding and publications. There was no change in teaching productivity (in two of five studies) in terms of educational output. Such strategies also resulted in increases in compensation at both individual and group levels (in three studies), with two studies reporting a change in distribution of compensation in favour of junior faculty. None of the studies assessed effects on administrative productivity or promotion processes. The overall quality of evidence was low. Interpretation: Strategies introduced to assess productivity as part of a compensation scheme appeared to improve productivity in research activities and possibly improved clinical productivity, but they had no effect in the area of teaching. Compensation increased at both group and individual levels, particularly among junior faculty. Higher quality evidence about the benefits and harms of such assessment strategies is needed., Academic productivity can be defined as a measurable output of a faculty member related to clinical, research, education or administrative activities. Achieving the best possible academic productivity is essential for [...]

Issues of financial and intellectual conflict of interest in clinical practice guidelines have raised increasing concern. Professional organizations have responded by more rigorous regulation of conflict of interest. Nevertheless, tension remains between the competing goals of optimizing guideline quality by using the experience and insight of experts and ensuring that financial and intellectual conflicts of interest do not influence recommendations. The executive committee of the American College of Chest Physicians' Antithromboric Guidelines has developed a strategy comprising 3 innovative aspects to address this tension: First, place equal emphasis on intellectual and financial conflicts and provide explicit criteria for both; second, a methodologist without important conflicts of interest should have primary responsibility for each chapter; and third, experts with important financial or intellectual conflicts of interest can collect and interpret evidence, but only panel members without important conflicts can be involved in developing the recommendation for a specific question. These strategies may help to achieve the benefits of expert input without conflicts of interest influencing recommendations.

The article focuses on Khalida Said who enjoys all qualities because she is an intellectual in the true sense of the term. Topics include considered she has deep specialist knowledge of every creative field she happens to be interested in and is thoroughly aware of all its trends, movements and profound internal specificities.

Soil-steel composite bridges (SSCBs) use the surrounding soil and the culvert’s flexible corrugated steel thin plates to support vertical loads above the culvert. Existing codes use empirical equations based on field measurements and full-scale tests for small and ordinary span SSCBs to estimate the arching process and how it distributes vertical stresses on the culvert walls. The empirical equations then compute the design straining actions. Recent developments in construction technology and urbanization have led to a significant increase in typical spans of SSCBs. This paper investigates large span SSCBs and the associated induced arching action using three-dimensional finite element analysis (FEA). The study compares the FEA findings of straining actions for large span SSCB case studies to the calculations of valid design codes. The comparison demonstrates that existing codes fail to predict the real arching mechanism and, consequently, the resulting straining actions. In addition, the FEA results illustrate how the arching mechanism varies as the span changes. Arching action is typically positive for relatively small spans but becomes negative as the span increases. Finally, results prove that current codes cannot accurately predict real arching, leading to inappropriate design straining actions. For large span SSCBs, these codes require modifications for the arching factors and the profile aspect ratio factors.

Background Cancer and pulmonary tuberculosis are major global health concerns and are associated with substantial morbidity and mortality. The association between active tuberculosis and subsequent cancer development has been investigated for many years. This study was planned to determine the prevalence of latent tuberculosis infection in patients with recently diagnosed bronchogenic carcinoma.Methods Sixty-four newly diagnosed primary lung cancer patients were enrolled. Diagnosis of latent tuberculosis infection was performed with QuantiFERON-TB Gold In-Tube tests, with exclusion of active tuberculosis.Results Latent tuberculosis infection was detected in 16 (25%) patients, and 8 (12.5%) had indeterminate results of the QuantiFERON-TB Gold In-Tube test. Being a current smoker was associated with a higher prevalence of latent tuberculosis (p= 0.001). Comorbidities, tumor site, and histopathology were not associated with latent tuberculosis infection.Conclusions There is a considerable risk of concurrent latent tuberculosis in newly diagnosed primary bronchogenic carcinoma. The need for treatment of latent tuberculosis in these patients and its influence on the outcome and prognosis are issues for further investigations.