Gammelgaardmortensen4332

Moreover, IL-17-dependent skin inflammation was mediated through IL-36 receptor and keratinocyte MyD88 signaling.

Using a new skin infection model, it is shown that Malassezia-induced IL-17- dependent skin inflammation and control of fungal infection are mediated via keratinocyte IL-36 receptor/MyD88 signaling.

Using a new skin infection model, it is shown that Malassezia-induced IL-17- dependent skin inflammation and control of fungal infection are mediated via keratinocyte IL-36 receptor/MyD88 signaling.

Our purpose was to evaluate the performance of the ACCU-CHEK® Inform II blood glucose monitoring system (Roche Diagnostics GmbH) compared with the perchloric acid hexokinase (PCA-HK) comparator method on the cobas® 6000 analyzer (Roche Diagnostics International Ltd) in critically ill patients.

Overall, 476 arterial (376 pediatric/adult, 100 neonate), 375 venous, and 100 neonatal heel-stick whole-blood samples were collected and evaluated from critical care settings at 10 US hospitals, including the emergency department, medical and surgical intensive care units (ICUs), and neonatal and pediatric ICUs. The ACCU-CHEK Inform II system was evaluated at 2 cutoff boundaries boundary 1 was ≥95% of results within ±12 mg/dL of the reference (samples with blood glucose <75 mg/dL) or ±12% of the reference (glucose ≥75 mg/dL), and boundary 2 was ≥98% of results within ±15 mg/dL or ±15% of the reference. Clinical performance was assessed by evaluating sample data using Parkes error grid, Monte Carlo simulation, and sensitivity and specificity analyses to estimate clinical accuracy and implications for insulin dosing when using the ACCU-CHEK Inform II system.

Proportions of results within evaluation boundaries 1 and 2, respectively, were 96% and 98% for venous samples, 94% and 97% for pediatric and adult arterial samples, 84% and 98% for neonatal arterial samples, and 96% and 100% for neonatal heel-stick samples. Clinical evaluation demonstrated high specificity and sensitivity, with low risk of potential insulin-dosing errors.

The ACCU-CHEK Inform II system demonstrated clinically acceptable performance against the PCA-HK reference method for blood glucose monitoring in a diverse population of critically ill patients in US care settings.

The ACCU-CHEK Inform II system demonstrated clinically acceptable performance against the PCA-HK reference method for blood glucose monitoring in a diverse population of critically ill patients in US care settings.Knowledge of the specificity of DNA-protein binding is crucial for understanding the mechanisms of gene expression, regulation and gene therapy. In recent years, deep-learning-based methods for predicting DNA-protein binding from sequence data have achieved significant success. Nevertheless, the current state-of-the-art computational methods have some drawbacks associated with the use of limited datasets with insufficient experimental data. To address this, we propose a novel transfer learning-based method, termed SAResNet, which combines the self-attention mechanism and residual network structure. More specifically, the attention-driven module captures the position information of the sequence, while the residual network structure guarantees that the high-level features of the binding site can be extracted. Meanwhile, the pre-training strategy used by SAResNet improves the learning ability of the network and accelerates the convergence speed of the network during transfer learning. The performance of SAResNet is extensively tested on 690 datasets from the ChIP-seq experiments with an average AUC of 92.0%, which is 4.4% higher than that of the best state-of-the-art method currently available. When tested on smaller datasets, the predictive performance is more clearly improved. Overall, we demonstrate that the superior performance of DNA-protein binding prediction on DNA sequences can be achieved by combining the attention mechanism and residual structure, and a novel pipeline is accordingly developed. The proposed methodology is generally applicable and can be used to address any other sequence classification problems.

Bowel dysfunction after rectal cancer surgery is common, with some experiencing low anterior resection syndrome (LARS) is common after rectal cancer surgery. This study examined if transanal total mesorectal excision (TaTME) has a similar risk of LARS and altered quality of life (QoL) as patients who undergo low anterior resection (LAR).

Patients who underwent TaTME or traditionally approached total mesorectal excision in a prospective colorectal cancer cohort study (2014-2019) were propensity score matched in a 1  1 ratio. LARS and QoL scores were assessed before and after surgery with a primary endpoint of major LARS at 12 months analysed for possible association between factors by logistic regression.

Of 61 TaTME and 317 LAR patients eligible, 55 from each group were propensity score matched. Higher LARS scores (30.6 versus 25.4, P = 0.010) and more major LARS (65 versus 42 per cent, P = 0.013; OR 2.64, 95 per cent c.i. 1.22 to 5.71) were reported after TaTME. Additionally, QoL score differences (body image, bowel frequency, and embarrassment) were worse in the TaTME group.

TaTME may be associated with more severe bowel dysfunction than traditional approaches to rectal cancer.

TaTME may be associated with more severe bowel dysfunction than traditional approaches to rectal cancer.

Early cancer detection is significant for the patient mortality rate reduction. Although machine learning has been widely employed in that context, there are still deficiencies. In this work, we studied different machine learning algorithms for early cancer detection and proposed an Adaptive Support Vector Machine (ASVM) method by synergizing Shuffled Frog Leaping Algorithm (SFLA) and Support Vector Machine (SVM) in this paper.

As ASVM regulates SVM for parameter adaption based on data characteristics, the experimental results demonstrated the robust generalization capability of ASVM on different datasets under different settings; for instance, ASVM can enhance the sensitivity by over 10% for early cancer detection compared with SVM. Besides, our proposed ASVM outperformed Grid Search + SVM and Random Search + SVM by significant margins in terms of the area under the ROC curve (AUC) (0.938 vs. 0.922 vs. 0.921).

The proposed algorithm and dataset are available at https//github.com/ElaineLIU-920/ASVM-for-Early-Cancer-Detection.

Supplementary data are available at Bioinformatics online.

Supplementary data are available at Bioinformatics online.

This study investigated whether a supervised exercise programme improves quality of life (QoL), fatigue and cardiorespiratory fitness in patients in the first year after oesophagectomy.

The multicentre PERFECT trial randomly assigned patients to an exercise intervention (EX) or usual care (UC) group. EX patients participated in a 12-week moderate- to high-intensity aerobic and resistance exercise programme supervised by a physiotherapist. Primary (global QoL, QoL summary score) and secondary (QoL subscales, fatigue and cardiorespiratory fitness) outcomes were assessed at baseline, 12 and 24 weeks and analysed as between-group differences using either linear mixed effects models or ANCOVA.

A total of 120 patients (mean(s.d.) age 64(8) years) were included and randomized to EX (61 patients) or UC (59 patients). Patients in the EX group participated in 96 per cent (i.q.r. 92-100 per cent) of the exercise sessions and the relative exercise dose intensity was high (92 per cent). At 12 weeks, beneficial EX effects were found for QoL summary score (3.5, 95 per cent c.i. 0.2 to 6.8) and QoL role functioning (9.4, 95 per cent c.i. 1.3 to 17.5). Global QoL was not statistically significant different between groups (3.0, 95 per cent c.i. -2.2 to 8.2). Physical fatigue was lower in the EX group (-1.2, 95 per cent c.i. -2.6 to 0.1), albeit not significantly. There was statistically significant improvement in cardiorespiratory fitness following EX compared with UC (peak oxygen uptake (1.8 ml/min/kg, 95 per cent c.i. 0.6 to 3.0)). After 24 weeks, all EX effects were attenuated.

A supervised exercise programme improved cardiorespiratory fitness and aspects of QoL.

Dutch Trial Register NTR 5045 (www.trialregister.nl/trial/4942).

Dutch Trial Register NTR 5045 (www.trialregister.nl/trial/4942).

Alpha-diketones such as diacetyl and 2,3-pentanedione have been used as artificial flavorings in a variety of industries and are produced naturally when food products such as coffee beans are roasted. Exposure to these compounds has been associated with bronchiolitis obliterans, a rare and severe respiratory disease. In the current paper, we (i) evaluate which steps in the coffee production process are associated with the highest alpha-diketone emissions at a small craft coffee roaster and associated café, (ii) determine the extent to which direct-reading measurements of CO, CO2, and total volatile organic compounds (VOCs) can serve as lower-cost surrogate indicators for diacetyl concentrations, and (iii) conduct a limited emissions study to quantify the effect that the process variable of roast type has on diacetyl emissions from grinding beans.

Exposure and area concentration data for diacetyl and 2,3-pentanedione were collected over 4 days of sampling at a single coffee roaster and associated café. Addilar studies at other small-scale craft coffee roasters and cafés to better understand the variability in these emissions and exposures within these types of facilities.The aim of this study was to evaluate dermal and respiratory exposure of workers to Lufenuron during spraying and re-entry on ornamental plants (stapling) in greenhouses. Potential and real skin exposure were evaluated using filter paper pads, hand contamination by washing, and respiratory exposure by personal air sampling. Dislodgeable foliar residues (DFRs) during re-entry were determined in order to calculate the dermal transfer factor (DTF). Lufenuron was analysed by liquid chromatography-mass detection. Respiratory dose (ReD) was calculated on the basis of a lung ventilation of 15-20 l min-1 and absorbed doses assuming a skin penetration of 13% and a respiratory retention of 100%. During stapling, from the dependence of exposure of hands from DFRs, the mean DTF was 0.575 cm2 h-1 (geometric mean). The ReD was 68.7-74.6 and 0.022-0.636% of the total real dose during spraying and stapling, respectively. The absorbed doses, 0.144-0.171 and 0.005-0.124 µg kg bw-1 during spraying and stapling, respectively, were less than the acceptable operator exposure level of 10 µg kg bw-1. Proper use of equipment and personal protective equipment and personal hygiene are aspects of fundamental importance on which workers must be trained. Adequate occupational hygiene studies are needed to support and verify working practices.Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.Dopamine is a prototypical neuromodulator that controls circuit function through G protein-coupled receptor signalling. Neuromodulators are volume transmitters, with release followed by diffusion for widespread receptor activation on many target cells. Yet, we are only beginning to understand the specific organization of dopamine transmission in space and time. Although some roles of dopamine are mediated by slow and diffuse signalling, recent studies suggest that certain dopamine functions necessitate spatiotemporal precision. Here, we review the literature describing dopamine signalling in the striatum, including its release mechanisms and receptor organization. We then propose the domain-overlap model, in which release and receptors are arranged relative to one another in micrometre-scale structures. This architecture is different from both point-to-point synaptic transmission and the widespread organization that is often proposed for neuromodulation. It enables the activation of receptor subsets that are within micrometre-scale domains of release sites during baseline activity and broader receptor activation with domain overlap when firing is synchronized across dopamine neuron populations. This signalling structure, together with the properties of dopamine release, may explain how switches in firing modes support broad and dynamic roles for dopamine and may lead to distinct pathway modulation.Fine-tuning cellular physiology in response to intracellular and environmental cues requires precise temporal and spatial control of gene expression. High-resolution imaging technologies to detect mRNAs and their translation state have revealed that all living organisms localize mRNAs in subcellular compartments and create translation hotspots, enabling cells to tune gene expression locally. Therefore, mRNA localization is a conserved and integral part of gene expression regulation from prokaryotic to eukaryotic cells. In this Review, we discuss the mechanisms of mRNA transport and local mRNA translation across the kingdoms of life and at organellar, subcellular and multicellular resolution. We also discuss the properties of messenger ribonucleoprotein and higher order RNA granules and how they may influence mRNA transport and local protein synthesis. Finally, we summarize the technological developments that allow us to study mRNA localization and local translation through the simultaneous detection of mRNAs and proteins in single cells, mRNA and nascent protein single-molecule imaging, and bulk RNA and protein detection methods.Stromal progenitors are found in many different tissues, where they play an important role in the maintenance of tissue homeostasis owing to their ability to differentiate into parenchymal cells. These progenitor cells are differentially pre-programmed by their tissue microenvironment but, when cultured and stimulated in vitro, these cells - commonly referred to as mesenchymal stromal cells (MSCs) - exhibit a marked plasticity to differentiate into many different cell lineages. Loss-of-function studies in vitro and in vivo have uncovered the involvement of specific signalling pathways and key transcriptional regulators that work in a sequential and coordinated fashion to activate lineage-selective gene programmes. Recent advances in omics and single-cell technologies have made it possible to obtain system-wide insights into the gene regulatory networks that drive lineage determination and cell differentiation. These insights have important implications for the understanding of cell differentiation, the contribution of stromal cells to human disease and for the development of cell-based therapeutic applications.Nowadays, the landscape of cancer treatments has broadened thanks to the clinical application of immunotherapeutics. After decades of failures, cancer immunotherapy represents an exciting alternative for those patients suffering from a wide variety of cancers, especially for those skin cancers, such as the early stages of melanoma. However, those cancers affecting internal organs still face a long way to success, because of the poor biodistribution of immunotherapies. Here, nanomedicine appears as a hopeful strategy to modulate the biodistribution aiming at target organ accumulation. In this way, efficacy will be improved, while reducing the side effects at the same time. In this review, we aim to highlight the most promising cancer immunotherapeutic strategies. From monoclonal antibodies and their traditional use as targeted therapies to their current use as immune checkpoint inhibitors; as well as adoptive cell transfer therapies; oncolytic viruses, and therapeutic cancer vaccination. Then, we aim to discuss the important role of nanomedicine to improve the performance of these immunotherapeutic tools to finally review the already marketed nanomedicine-based cancer immunotherapies.Private Coe of the Army Dental Corps is thought to be the first soldier in the British Army to escape captivity in the Second World War and achieve the 'home run' back to the UK. He was captured near Dunkirk on 30 May 1940 by the German Army and was transported to camp Stalag XXA (Thorn) in Poland. He successfully escaped from the prisoner of war camp and made his way back to the United Kingdom. King George VI thought the escape a fine performance on the part of Private Coe and awarded him the Distinguished Conduct Medal.The specialist cadre of the Royal Army Dental Corps (RADC) came to fruition at the start of World War II, with the speciality of maxillofacial surgery being born during World War I. The cadre has followed developments within the speciality, and building on the experience of forebears, has become capable of not only providing a secondary care service to the RADC but also being competent in the management of complex war injuries.By 1921, dentistry within the British military had finally been formalised under the Army Dental Corps. From this point on and throughout the Second World War, significant changes took place. This was due to the mass demand for dental care, professionals to deploy to all situations and adapting equipment to work outside of a classical clinical setting - all to ensure service personnel were fit to deploy or return to the front line as soon as possible. This article will look briefly into these changes and sets the scene to highlight four outstanding dental officers, the adversity faced and their heroic acts of bravery that earned them the Military Cross.Operation Herrick was the British military operation in Afghanistan that occurred between 2002 and 2014; the most recent, large-scale and publicly conducted war in British history. During this time, over 60 British military dental teams deployed as part of the UK Medical Group, their primary role being the treatment of dental emergencies in UK Armed Forces. There are numerous publications citing statistics regarding the rates and nature of dental casualties on operations, their management and how this affects operational capability. This article instead aims to give a more generalised insight into the lived experience of an Army dentist deployed on Operation Herrick.This article provides insights into the life and experiences of two British Army dental officers who were both imprisoned at Colditz during World War II. Eric Cooper and Julius Green were in the early years of their careers as dentists when World War II began. They joined the Army Dental Corps and both were captured by Germans and held as prisoners of war at various locations. The last place they were imprisoned until the end of the war was Colditz. They both survived to share their stories which are summarised here.This article tells the story of Captain David Arkush who was a dental officer in the Army Dental Corps during World War II. He was posted to Singapore in 1941 and was present at the fall of Singapore when he was subsequently captured by the Japanese and became a prisoner of war on the Burmese Railway. Living conditions were horrific but he was able to provide basic dentistry during this difficult time. The following is a first-hand account of Arkush's story, as told in his own words. The material came from recordings of an interview with Arkush in 2011 when he was 96 years old. Some of the dates have been altered to allow for historical accuracy, but all other details have been reported as told.A summary of the British Army's contribution to dental provision for Commonwealth troops engaged in the Korean War including the personal recollections of James Donaldson, a Royal Army Dental Corps veteran. It outlines the planning and setting up of dental facilities in the theatre of war, some of the problems encountered and how these were overcome while operating under difficult and, at times, extreme weather conditions.The Royal Army Dental Corps (RADC) provides dental care to the British Army both in barracks and on deployment While a significant proportion of most RADC dental officers' careers is spent working in permanent military primary care dental clinics, it is the ability of all RADC dental officers to provide dental care when deployed that provides unique challenges only seen in the military environment. All RADC dental officers are able to deliver high quality care in temporary facilities. During a career the majority of RADC dental officers will have at least one job in a medical regiment providing the dental component of the British Army's rapidly deployable medical capability. This article covers some of the issues faced when delivering dental care outside the UK using portable equipment on a recent exercise.As RADC officers gain experience they are expected to lead increasingly large teams, both within primary care dentistry and some in the wider Army Medical Services, with the appropriate professional and military training to support their development.Working under pressure can be developed through the use of adventurous training and sport and the authors have pushed themselves well beyond their comfort zones in the air, on land and under the sea.This is the tale of two soldiers serving in the Army Dental Corps, who conducted an unsupported and unauthorised commando mission into occupied France during World War II (WW2).In 1942, Sergeant King and Private Cuthbertson planned and executed one of the most daring and ambitious raids of WW2. Their perceived lack of utility to the war effort spawned their personal invasion of France, which became of interest to not only the Special Operations Executive (SOE), but Winston Churchill himself. The couple stole weapons from the armoury, commandeered a vessel, and journeyed to France where they inflicted damage and disruption to the enemy.Their mission caused ripples of pride throughout those serving, especially those in the Army Dental Corps. The question still remains though; should they have been treated as heroes or villains?The First Gulf War was triggered by Iraq, led by Saddam Hussein, invading and brutally occupying Kuwait, triggering an international response. A coalition of UN-sponsored allies, led by the USA, assembled to liberate Kuwait. The forces in the region included a British contingent, initially focusing on an Armoured Brigade, but eventually expanding to an Armoured Division, supported by maritime and air components. The Army presence included Royal Army Dental Corps officers and soldiers in clinical roles, but also as medical sub-unit commanders. A brief account of the field organisation of the Army Medical Services and the varied roles played by dental personnel leads into a short clinical report which provides epidemiological information on the dental health of the force and data on the treatment carried out. A description of the preparation for war is followed by a personal narrative of the land campaign.Peacekeeping and the delivery of humanitarian aid is a vital component in the repertoire of any modern military and the UK has been at the forefront in contributing to these types of operation at an international level. When preparing for an enduring task such as peacekeeping, it is essential to consider all supporting components that can help deliver a common goal. Whether access to healthcare for the local population has collapsed or maintaining a healthy deployed force, dentistry will inevitably need to be considered and appropriate provision secured.This paper aims to look at the deployed dental support provided to recent peacekeeping interventions by the British Army.At the time of the Falklands Campaign (Operation Corporate), apart from performing clinical dentistry, the Royal Army Dental Corps (RADC) dental officer's combat role included acting as a resuscitation officer attached to a field hospital or a field ambulance. It was in that role that three dental officers from the RADC became involved in the campaign. This paper reflects their experiences in the operation.Oral disease can cause substantial disruption to service personnel, resulting in debilitation and reduced effectiveness while deployed on military operations. As such, Defence dentistry delivers an occupationally focused dental service that is deployable, agile and holistic, to ensure service personnel are dentally fit for operations and that the impact of dental morbidity is minimised.Defence dentists provide a unique service, balancing the needs of the individual while considering their operational role requirements. This enables the UK Armed Forces' oral health to be optimised by mitigating morbidity and maintaining operational capability while deployed.The aim of this paper is to highlight the key principles of Defence dentistry by discussing the public health values and occupational focus which underpin a patient-centred approach and the agility of the uniformed military dental workforce in providing a responsive and deployable care capability.Between 1661 and 1921, Britain witnessed significant changes in the prevalence of dental caries and its treatment. This period saw the formation of the standing British Army and its changing oral health needs. This paper seeks to identify these changes in the Army and its dental needs, and place them in the context of the changing disease prevalence and dental advances of the time. The rapidly changing military and oral health landscapes of the late nineteenth century and early twentieth century bring recognition of the Army's growing dental problems. It is not, however, without years of campaigning by members of the profession, huge dental morbidity rates on campaign and the outbreak of a global conflict that the War Office resource a solution. This culminates in 1921 with, for the first time in 260 years, the establishment of a professional Corps within the Army for the dental care of its soldiers; the Army Dental Corps is formed.Background Dental emergencies experienced during military operations may render individuals unable to operate effectively. To minimise this risk, UK Armed Forces (UKAF) recruits receive a prevention-focused dental care intervention during military training (known as 'Project MOLAR') before their entry to the trained strength of the Armed Forces.Aim To evaluate whether Project MOLAR is effective in preventing future dental emergency events and subsequent oral disease in UKAF recruits.Methods This is a retrospective cohort analysis of UKAF recruits who enlisted between 1 January 2011 and 31 December 2011, conducted by analysing electronic primary dental care records. Adverse outcomes were defined as i) incidence of dental emergency events during the five-year follow-up period; and ii) further oral disease at 18 months measured by an increase in Decayed, Missing and Filled Teeth (DMFT).Results In total, 7,361 recruits met the inclusion criteria. The total follow-up time for the cohort was 31,957 person-years (mean follow-up 4.3 years/recruit). Individuals whose treatment was completed under Project MOLAR were found to experience a 30% reduction in dental emergency incidence (RR 0.70-95% CI 0.63-0.76) (p less then 0.001) and a 64% reduction in the odds of DMFT increase at 18 months (OR 0.36-95% CI 0.28-0.47) (p less then 0.001) compared to individuals whose treatment was incomplete.Conclusions Defence dentistry's focus on delivering prevention-focused dentistry early in a recruit's military career confers a downstream benefit to personnel who complete the intervention, such that dental emergency occurrences and DMFT progression are significantly reduced.The ability to identify regulatory interactions that mediate gene expression changes through distal elements, such as risk loci, is transforming our understanding of how genomes are spatially organized and regulated. Capture Hi-C (CHi-C) is a powerful tool to delineate such regulatory interactions. However, primary analysis and downstream interpretation of CHi-C profiles remains challenging and relies on disparate tools with ad-hoc input/output formats and specific assumptions for statistical modeling. Here we present a data processing and interaction calling toolkit (CHiCANE), specialized for the analysis and meaningful interpretation of CHi-C assays. In this protocol, we demonstrate applications of CHiCANE to region capture Hi-C (rCHi-C) and promoter capture Hi-C (pCHi-C) libraries, followed by quality assessment of interaction peaks, as well as downstream analysis specific to rCHi-C and pCHi-C to aid functional interpretation. For a typical rCHi-C/pCHi-C dataset this protocol takes up to 3 d for users with a moderate understanding of R programming and statistical concepts, although this is dependent on dataset size and compute power available. CHiCANE is freely available at https//cran.r-project.org/web/packages/chicane .Next-generation sequencing has transformed our knowledge of the genetics of lymphoid malignancies. However, limited experimental systems are available to model the functional effects of these genetic changes and their implications for therapy. The majority of mature B-cell malignancies arise from the germinal center (GC) stage of B-cell differentiation. Here we describe a detailed protocol for the purification and ex vivo expansion of primary, nonmalignant human GC B cells. We present methodology for the high-efficiency transduction of these cells to enable combinatorial expression of putative oncogenes. We also describe alternative approaches for CRISPR-Cas9-mediated deletion of putative tumor suppressors. Mimicking genetic changes commonly found in lymphoid malignancies leads to immortalized growth in vitro, while engraftment into immunodeficient mice generates genetically customized, synthetic models of human lymphoma. The protocol is simple and inexpensive and can be implemented in any laboratory with access to standard cell culture and animal facilities. It can be easily scaled up to enable high-throughput screening and thus provides a versatile platform for the functional interrogation of lymphoma genomic data.Peptides are promising drug candidates because of their diversity, biocompatibility and spectrum of activities. Here, we describe a protocol for high-throughput screening of SPOT-peptide arrays to assess the antibiofilm, antimicrobial and immunomodulatory activities of synthetic peptides. It is a Protocol Extension of our previous Nature Protocols article, which describes the synthesis of SPOT-peptide arrays and assays for screening antimicrobial activity. This latest protocol allows the simultaneous assessment of hundreds of synthetic host defense peptides to define their overall activity profiles and identify candidate sequences that are suitable for further characterization and development as anti-infectives. When coupled with the SPOT-array technology for peptide synthesis, the described procedures are rapid, inexpensive and straightforward for peptide library screening. The protocols can be implemented in most microbiology or immunology research laboratories without the need for specialists. The time to complete each step ranges between 1 and 4 h with overnight pauses, and datasets related to the antibiofilm and immunomodulatory activities of a large set of peptide sequences can be generated in a few days.We have recently established that human norovirus (HuNoV) replicates efficiently in zebrafish larvae after inoculation of a clinical sample into the yolk, providing a simple and robust in vivo system in which to study HuNoV. In this Protocol Extension, we present a detailed description of virus inoculation by microinjection, subsequent daily monitoring and harvesting of larvae, followed by viral RNA quantification. This protocol can be used to study viral replication of genogroup (G)I and GII HuNoVs in vivo within 3-4 d. Additionally, we describe how to evaluate the in vivo antiviral effect and toxicity of small molecules using HuNoV-infected zebrafish larvae, in multi-well plates and without the need for specific formulations. This constitutes a great advantage for drug discovery efforts, as no specific antivirals or vaccines currently exist to treat or prevent norovirus gastroenteritis.

In colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk.

We measured 84 angiogenic and inflammatory markers in serum sampled at the time of diagnosis within the population-based cohort of 122 stage I-III patients. In a stepwise manner, the statistically strongest proteins associated with time to development of liver metastasis were analysed in the corresponding serum samples from 273 stage II-III rectal cancer patients in three independent cohorts.

We identified the soluble form of the costimulatory immune checkpoint receptor cluster of differentiation molecule 40 (sCD40) as a marker of liver metastasis risk across all patient cohorts-the higher the sCD40 level, the shorter time to liver metastasis. In patients receiving neoadjuvant treatment, the sCD40 value remained an independent variable associated with progression to liver metastasis along with the local treatment response. Of note, serum sCD40 was not associated with progression to lung metastasis.

Circulating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice.

Circulating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice.

Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of these associations.

Two, one and 14 independent single nucleotide polymorphisms associated with serum folate, vitamin B6 and vitamin B12 at the genome-wide significance threshold were selected as genetic instruments. Summary-level data for the associations of the vitamin-associated genetic variants with cancer were obtained from the UK Biobank study including 367,561 individuals and FinnGen consortium comprising up to 176,899 participants.

Genetically predicted folate and vitamin B6 concentrations were not associated with overall cancer, overall digestive system cancer or oesophageal, gastric, colorectal or pancreatic cancer. Genetically predicted vitamin B12 concentrations were positively associated with overall digestive system cancer (OR

, 1.12; 95% CI 1.04, 1.21, p = 0.003) and colorectal cancer (OR

1.16; 95% CI 1.06, 1.26, p = 0.001) in UK Biobank. Results for colorectal cancer were consistent in FinnGen and the combined OR

was 1.16 (95% CI 1.08, 1.25, p < 0.001). There was no association of genetically predicted vitamin B12 with any other site-specific digestive system cancers or overall cancer.

These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer.

These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer.

The prognosis for high-risk childhood acute leukaemias remains dismal and established treatment protocols often cause long-term side effects in survivors. This study aims to identify more effective and safer therapeutics for these patients.

A high-throughput phenotypic screen of a library of 3707 approved drugs and pharmacologically active compounds was performed to identify compounds with selective cytotoxicity against leukaemia cells followed by further preclinical evaluation in patient-derived xenograft models.

Auranofin, an FDA-approved agent for the treatment of rheumatoid arthritis, was identified as exerting selective anti-cancer activity against leukaemia cells, including patient-derived xenograft cells from children with high-risk ALL, versus solid tumour and non-cancerous cells. It induced apoptosis in leukaemia cells by increasing reactive oxygen species (ROS) and potentiated the activity of the chemotherapeutic cytarabine against highly aggressive models of infant MLL-rearranged ALL by enhancing DNA damage accumulation. The enhanced sensitivity of leukaemia cells towards auranofin was associated with lower basal levels of the antioxidant glutathione and higher baseline ROS levels compared to solid tumour cells.

Our study highlights auranofin as a well-tolerated drug candidate for high-risk paediatric leukaemias that warrants further preclinical investigation for application in high-risk paediatric and adult acute leukaemias.

Our study highlights auranofin as a well-tolerated drug candidate for high-risk paediatric leukaemias that warrants further preclinical investigation for application in high-risk paediatric and adult acute leukaemias.

This is a qualitative, phenomenological study.

To investigate media portrayal of spinal cord injury (SCI) as perceived by people with SCI and explore its impact on their lived experience.

People with SCI living in Australia.

Twenty-four participants, recruited using purposive and snowball sampling, completed in-depth, semi-structured interviews. Thematic data analysis followed an inductive, iterative process.

Participants perceived media portrayed SCI through a narrow lens, describing how people with SCI were 'absent' or portrayed as either 'pity or pedestal'. Participants said media portrayed an inaccurate picture of their lived experience that perpetuated misunderstandings of SCI. This portrayal fostered unreasonable public expectations and assumptions about living with SCI, which presented in the participant's lives as uncomfortable interactions and inappropriate remarks. The impact for participants was a burden to explain SCI and justify what it meant for them. People with SCI would like media ting narratives and raising awareness to diverse abilities of people with SCI.Immunotherapy has revolutionized cancer treatment, but efficacy remains limited in most clinical settings. Cancer is a systemic disease that induces many functional and compositional changes to the immune system as a whole. Immunity is regulated by interactions of diverse cell lineages across tissues. Therefore, an improved understanding of tumour immunology must assess the systemic immune landscape beyond the tumour microenvironment (TME). Importantly, the peripheral immune system is required to drive effective natural and therapeutically induced antitumour immune responses. In fact, emerging evidence suggests that immunotherapy drives new immune responses rather than the reinvigoration of pre-existing immune responses. However, new immune responses in individuals burdened with tumours are compromised even beyond the TME. Herein, we aim to comprehensively outline the current knowledge of systemic immunity in cancer.This study aimed to assess the reliability of opportunistic screening programs in estimating the prevalence, treatment, and control rate of hypertension in the general population. Two recent epidemiological surveys obtained data on hypertension in the adult general population in Greece. The EMENO (2013-2016) applied a multi-stage stratified random sampling method to collect nationwide data. The MMM (2019) collected data through opportunistic (voluntary) screening in five large cities. Hypertension was defined as blood pressure (BP) ≥ 140/90 mmHg (single occasion; average of 2nd-3rd measurement; electronic devices) and/or use of antihypertensive drugs. Data from a total of 10,426 adults were analyzed (EMENO 4,699; MMM 5,727). Mean age (SD) was 49.2 (18.6)/52.7 (16.6) years (EMENO/MMM, p  less then  0.001), men 48.6/46.5% (p  less then  0.05) and body mass index 28.2 (5.7)/27.1 (5.0) kg/m2 (p  less then  0.001). The prevalence of hypertension in ΕΜΕΝΟ/MMM was 39.6/41.6% (p  less then  0.05) and was higher in men (42.7/50.9%, p  less then  0.001) than in women (36.5/33.6%, p  less then  0.05). Among hypertensive subjects, unaware were 31.8/21.3% (EMENO/MMM, p  less then  0.001), aware untreated 2.7/5.6% (p  less then  0.001), treated uncontrolled 35.1/24.8% (p  less then  0.001), and treated controlled 30.5/48.3% (p  less then  0.001). In conclusion, the prevalence of hypertension was similar with random sampling (EMENO) and opportunistic screening (MMM). However, opportunistic screening underestimated the prevalence of undiagnosed hypertension and overestimated the rate of hypertension treatment and control. Thus, random sampling national epidemiological studies are necessary for assessing the epidemiology of hypertension. Screening programs are useful for increasing awareness of hypertension in the general population, yet the generalization of such findings should be interpreted with caution.Rather than being mere biomarkers reflecting generalized vascular injury, endothelial- (EMVs) and platelet-derived (PMVs) microvesicles have emerged as potent regulators of intercellular communication with significant biologic effects in vascular homeostasis and several pathophysiological responses including inflammation and thrombosis. So far, studies in hypertension are scarce, whereas no studies exist in masked hypertension (MH). We measured EMVs and PMVs in untreated, newly diagnosed hypertensives (HTs) and MHs compared to normotensive controls (NTs), and associated them with various cardiovascular risk factors. Sustained hypertension (SHT) and MH were defined according to standard blood pressure (BP) criteria. All HTs were free of cardiovascular disease and medications. Microvesicles' quantitation and detection were performed by flow cytometry by using cell-specific antibodies and corresponding isotypes (anti-CD105 and anti-CD144 for EMVs, anti-CD42a for PMVs, and Annexin V-fluorescein isothiocyanate for all microvesicles). In this study, we included 59 HTs (44 SHTs and 15 MHs) and 27 NTs. HTs had significantly elevated EMVs (p = 0.004), but not PMVs compared to NTs. MHs had significantly elevated EMVs compared to NTs (p = 0.012) but not compared to SHTs. Furthermore, EMVs significantly correlated with ambulatory (r = 0.214-0.284), central BP (r = 0.247-0.262), and total vascular resistance (r = 0.327-0.361). EMVs are increased not only in SHTs but also in MHs, a hypertension phenotype with a cardiovascular risk close to SHT. EMVs have emerged as active contributors to thromboinflammation and vascular damage and may explain, in part, the adverse cardiovascular profile of SHTs and MHs.Identifying patients with hypertension at high risk of cardio-metabolic multi-morbidity (CMM) is key for intervention. We examined the independent association of CMM with ethnicity and socioeconomic status (SES) among patients with uncontrolled hypertension. Demographic, socioeconomic, lifestyle, and clinical factors were obtained from 921 patients aged ≥40 years with hypertension in the multiethnic Singapore. CMM was defined as having ≥2 chronic diseases (diabetes mellitus, heart disease, stroke, and chronic kidney disease), which were confirmed by medical records or laboratory measurements. The overall CMM prevalence was 20.9% (95% confidence interval [CI] 18.4-23.6%). The CMM prevalence was higher in Malays (27.1%) and Indians (30.2%) than Chinese (18.8%), and it was higher among patients with lower SES (ranging from 21.3 to 23.9% using education, employment status, housing ownership and housing types as proxies) compared to those with higher SES (13.1-20.8%). In a multivariate model comprising demographic and socioeconomic factors (age, sex, ethnicity and SES), higher CMM odds were independently associated with ethnic minorities (Malays [OR 1.81; 95% CI 1.10-2.98] or Indians [OR 2.21; 95% CI 1.49-3.29] vs. Chinese) and lower SES (unemployment [OR 1.45; 95% CI 1.02-2.05] and residing in smaller public housing [OR 1.95; 95% CI 1.16-3.28]). Other correlates of CMM included age, men, central obesity, and poorer dietary quality (lower fruits and vegetables intakes). CMM affected one out of five patients with hypertension in Singapore. Intervention programs should target patients with hypertension, particularly those of ethnic minorities and from lower socioeconomic strata.The performance of Omron HEM-9200T for monitoring blood pressure (BP) in the upper arm was validated in accordance with the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-22013 protocol. The device was assessed by using it on 87 participants who fulfilled the inclusion criteria involving the ranges of arm circumference and systolic and diastolic BP provided by the protocol. Validation and data analysis were performed according to the protocol. In the ANSI/AAMI/ISO 81060-22013 validation procedure (criterion 1), the mean ± standard deviation of the differences between the test device and reference BP was -0.1 ± 5.06/1.2 ± 5.8 mmHg (systolic/diastolic). The mean differences between the two observers and Omron HEN-9200T were -0.1 ± 3.82 mmHg for systolic BP and 1.2 ± 5.34 mmHg for diastolic BP, fulfilling criterion 2 with an SD of ≤6.91 for SBP and ≤6.87 for DBP. These two ANSI/AAMI/ISO criteria were fulfilled.The Omron HEM-9200T BP monitor fulfilled the requirements of the ANSI/AAMI/ISO validation standard and can be recommended for BP measurements at home in the general population.Chromosomal instability leading to aneuploidy is pervasive in early human embryos1-3 and is considered as a major cause of infertility and pregnancy wastage4,5. Here we provide several lines of evidence that blastocysts containing aneuploid cells are worthy of in vitro fertilization transfer. First, we show clinically that aneuploid embryos can lead to healthy births, suggesting the presence of an in vivo mechanism to eliminate aneuploidy. Second, early development and cell specification modelled in micropatterned human 'gastruloids' grown in confined geometry show that aneuploid cells are depleted from embryonic germ layers, but not from extraembryonic tissue, by apoptosis in a bone morphogenetic protein 4 (BMP4)-dependent manner. Third, a small percentage of euploid cells rescues embryonic tissue in mosaic gastruloids when mixed with aneuploid cells. Finally, single-cell RNA-sequencing analysis of early human embryos revealed a decline of aneuploidy beginning on day 3. Our findings challenge two current dogmas that a single trophectoderm biopsy at blastocyst stage to perform prenatal genetic testing can accurately determine the chromosomal make-up of a human embryo, and that aneuploid embryos should be withheld from embryo transfer in association with in vitro fertilization.R-loops are non-B DNA structures with intriguing dual consequences for gene expression and genome stability. In addition to their recognized roles in triggering DNA double-strand breaks (DSBs), R-loops have recently been demonstrated to accumulate in cis to DSBs, especially those induced in transcriptionally active loci. In this Review, we discuss whether R-loops actively participate in DSB repair or are detrimental by-products that must be removed to avoid genome instability.Rewiring of cellular programmes in malignant cells generates cancer-specific vulnerabilities. Here, using an unbiased screening strategy aimed at identifying non-essential genes required by tumour cells to sustain unlimited proliferative capacity, we identify the male-specific lethal (MSL) acetyltransferase complex as a vulnerability of genetically unstable cancers. We find that disruption of the MSL complex and consequent loss of the associated H4K16ac mark do not substantially alter transcriptional programmes but compromise chromosome integrity and promote chromosomal instability (CIN) that progressively exhausts the proliferative potential of cancer cells through a p53-independent mechanism. This effect is dependent on pre-existing genomic instability, and normal cells are insensitive to MSL disruption. Using cell- and patient-derived xenografts from multiple cancer types, we show that excessive CIN induced by MSL disruption inhibits tumour maintenance. Our findings suggest that targeting MSL may be a valuable means to increase CIN beyond the level tolerated by cancer cells without inducing severe adverse effects in normal tissues.De novo blood vessel formation occurs through coalescence of endothelial cells (ECs) into a cord-like structure, followed by lumenization either through cell-1-3 or cord-hollowing4-7. Vessels generated in this manner are restricted in diameter to one or two ECs, and these models fail to explain how vasculogenesis can form large-diameter vessels. Here, we describe a model for large vessel formation that does not require a cord-like structure or a hollowing step. In this model, ECs coalesce into a network of struts in the future lumen of the vessel, a process dependent upon bone morphogenetic protein signalling. The vessel wall forms around this network and consists initially of only a few patches of ECs. To withstand external forces and to maintain the shape of the vessel, strut formation traps erythrocytes into compartments to form a rigid structure. Struts gradually prune and ECs from struts migrate into and become part of the vessel wall. Experimental severing of struts resulted in vessel collapse, disturbed blood flow and remodelling defects, demonstrating that struts enable the patency of large vessels during their formation.Quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) using Tc-99m pertechnetate aids in evaluating salivary gland function. However, gland segmentation and quantitation of gland uptake is challenging. We develop a salivary gland SPECT/CT with automated segmentation using a deep convolutional neural network (CNN). The protocol comprises SPECT/CT at 20 min, sialagogue stimulation, and SPECT at 40 min post-injection of Tc-99m pertechnetate (555 MBq). The 40-min SPECT was reconstructed using the 20-min CT after misregistration correction. Manual salivary gland segmentation for %injected dose (%ID) by human experts proved highly reproducible, but took 15 min per scan. An automatic salivary segmentation method was developed using a modified 3D U-Net for end-to-end learning from the human experts (n = 333). The automatic segmentation performed comparably with human experts in voxel-wise comparison (mean Dice similarity coefficient of 0.81 for parotid and 0.79 for submandibular, respectively) and gland %ID correlation (R2 = 0.