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Background Evidence is lacking for safe and effective treatments for juvenile localised scleroderma (JLS). Methotrexate (MTX) is commonly used first line and mycophenolate mofetil (MMF) second line, despite a limited evidence base. A head to head trial of these two medications would provide data on relative efficacy and tolerability. However, a frequentist approach is difficult to deliver in JLS, because of the numbers needed to sufficiently power a trial. A Bayesian approach could be considered. Methods An international consensus meeting was convened including an elicitation exercise where opinion was sought on the relative efficacy and tolerability of MTX compared to MMF to produce prior distributions for a future Bayesian trial. Secondary aims were to achieve consensus agreement on critical aspects of a future trial. Results An international group of 12 clinical experts participated. Opinion suggested superior efficacy and tolerability of MMF compared to MTX; where most likely value of efficacy of MMF was 0.70 (95% confidence interval (CI) 0.34-0.90) and of MTX was 0.68 (95% CI 0.41-0.8). The most likely value of tolerability of MMF was 0.77 (95% CI 0.3-0.94) and of MTX was 0.62 (95% CI 0.32-0.84). The wider CI for MMF highlights that experts were less sure about relative efficacy and tolerability of MMF compared to MTX. Despite using a Bayesian approach, power calculations still produced a total sample size of 240 participants, reflecting the uncertainty amongst experts about the performance of MMF. Conclusions Key factors have been defined regarding the design of a future Bayesian approach clinical trial including elicitation of prior opinion of the efficacy and tolerability of MTX and MMF in JLS. Combining further efficacy data on MTX and MMF with prior opinion could potentially reduce the pre-trial uncertainty so that, when combined with smaller trial sample sizes a compelling evidence base is available.

Abstract Background Plasmodium falciparum exhibits resistance to the artemisinin component of the frontline antimalarial treatment Artemisinin-based Combination Therapy in South East Asia. Millions of lives will be at risk if artemisinin resistance (ART-R) spreads to Africa. Single non-synonymous mutations in the propeller region of PF3D7_1343700,“K13” are implicated in resistance. In this work, we use transcriptional profiling to characterize a laboratory-generated k13 insertional mutant previously demonstrated to have increased sensitivity to artemisinins to explore the functional role of k13. Results A set of RNA-seq and microarray experiments confirmed that the expression profile of k13 is specifically altered during the early ring and early trophozoite stages of the mutant intraerythrocytic development cycle. The down-regulation of k13 transcripts in this mutant during the early ring stage is associated with a transcriptome advance towards a more trophozoite-like state. To discover the specific downstream effect of k13 dysregulation, we developed a new computational method to search for differential gene expression while accounting for the temporal sequence of transcription. We found that the strongest biological signature of the transcriptome shift is an up-regulation of DNA replication and repair genes during the early ring developmental stage and a down-regulation of DNA replication and repair genes during the early trophozoite stage; by contrast, the expressions of housekeeping genes are unchanged. This effect, due to k13 dysregulation, is antagonistic, such that k13 levels are negatively correlated with DNA replication and repair gene expression. Conclusion Our results support a role for k13 as a stress response regulator consistent with the hypothesis that artemisinins mode of action is oxidative stress and k13 as a functional homolog of Keap1 which in humans regulates DNA replication and repair genes in response to oxidative stress.

Abstract Objective To quantify the impact of inflammatory brain diseases in the pediatric population on health-related quality of life, including the subdomains of physical, emotional, school and social functioning. Methods This was a multicenter, observational cohort study of children (

ABSTRACT Malaria remains one of the most devastating parasitic diseases worldwide, with 90% of the malaria deaths in Africa in 2013 attributable to Plasmodium falciparum. The clinical symptoms of malaria include cycles of fever, corresponding to parasite rupture from red blood cells every 48 h. Parasite pathways involved in the parasite’s ability to survive the host fever response, and indeed, the functions of ~40% of P. falciparum genes as a whole, are still largely unknown. Here, we evaluated the potential of scalable forward-genetic screening methods to identify genes involved in the host fever response. We performed a phenotypic screen for genes linked to the parasite response to febrile temperatures by utilizing a selection of single-disruption P. falciparum mutants generated via random piggyBac transposon mutagenesis in a previous study. We identified several mutants presenting significant phenotypes in febrile response screens compared to the wild type, indicating possible roles for the disrupted genes in this process. We present these initial studies as proof that forward genetics can be used to gain insight into critical factors associated with parasite biology. IMPORTANCE Though the P. falciparum genome sequence has been available for many years, ~40% of its genes do not have informative annotations, as they show no detectable homology to those of studied organisms. More still have not been evaluated via genetic methods. Scalable forward-genetic approaches that allow interrogation of gene function without any pre-existing knowledge are needed to hasten understanding of parasite biology, which will expedite the identification of drug targets and the development of future interventions in the face of spreading resistance to existing frontline drugs. In this work, we describe a new approach to pursue forward-genetic phenotypic screens for P. falciparum to identify factors associated with virulence. Future large-scale phenotypic screens developed to probe other such interesting phenomena, when considered in parallel, will prove a powerful tool for functional annotation of the P. falciparum genome, where so much remains undiscovered.

Neuromorphic vision sensors, commonly referred to as Event Cameras (ECs), have gained prominence as a field of research in Computer Vision. This popularity stems from the numerous unique characteristics including High Dynamic Range, High Temporal Resolution, and Low Latency. Of particular interest is their temporal resolution, which proves ideal for human monitoring applications. Capturing rapid facial movements and eye gaze can be effectively achieved with ECs. Recent studies involving the use of ECs for object detection and tracking have demonstrated success in tasks involving Eye Motion Analysis such as Eye tracking, Blink detection, Gaze estimation and Pupil tracking. The objective of this study is to provide a comprehensive review of the current research in the aforementioned tasks, focusing on the potential utilization of ECs for future tasks involving rapid eye motion detection, such as detection and classification of saccades. We highlight studies that may serve as a foundation for undertaking such a task, such as pupil tracking and gaze estimation. We also highlight in our review some common challenges encountered such as the availability of datasets and review some of the methods used in solving this problem. Finally, we discuss some limitations of this field of research and conclude with future directions including real-world applications and potential research directions.

Since January 2005, H3N2 influenza viruses have been isolated from pigs and turkeys throughout Canada and from a swine farmer and pigs on the same farm in Ontario. These are [...]

The stabilization and treatment of vertebral compression fractures via vertebroplasty procedure foresees the injection of bone cements and recent research is focused on the use of degradable cements featuring an appropriate degradation kinetics. This study presents an investigation into the degradation behaviour of a resorbable ceramic composite cement based on calcium sulphate hemihydrate (CSH), supplemented with strontium-containing mesoporous bioactive glasses (Sr-MBG) and zirconia nanoparticles (ZrO2). The alterations in the material's microstructure resulting from the degradation process were thoroughly analysed using two image analysis techniques. Micro-computed tomography (Micro-CT) was employed for scanning, while CT-An software associated with the instrument and a Python-coded image analysis tool were utilised to assess porosity and pore size distribution over time. Comparative analysis of the obtained results demonstrated the efficacy of both techniques in comprehensively understanding the internal microstructural changes and volume variations during the degradation of the ceramic composite cement.

BackgroundMitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.MethodsWe report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.ResultsThe patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.ConclusionsWe developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.

This paper explores the awareness, knowledge, attitudes and behaviour of members of the Irish fishing community towards environmental topics such as; microplastics, plastic pollution and recycling. We conducted a mixed method survey consisting of 26 questions (2021) involving members of the Irish fishing community (fishers, aquaculturists etc.). Respondents were generally aware of microplastics and the threats they can pose to different environmental matrices. They noticed litter frequently when engaged in their fishing activities (0% never noticed litter) and in large quantities (35% of respondents noticed over 10+ items) but they were likely (likely 40% and highly likely 35%) to remove it from the environment. Durability was the main reason for the selection of most fishing plastics used by respondents (ranked first in 4 of 5 plastic items) while recyclability played a lesser role. Respondents also viewed plastics as cheap and convenient with these terms accounting for 48% of positive connotations related to the word ‘plastic’, however, in general associated plastic with negative phrases. Barriers to the recycling of used fishing plastics were most frequently identified as being due to a lack of knowledge on how to or a lack of facilities. This study provides novel insight into a previously unstudied cohort in Irish society towards plastics and recycling and can serve as guidance for further work on this group.

Natural killer (NK) cells, which are an exciting alternative cell source for cancer immunotherapies, must sense and respond to their physical environment to traffic to and eliminate cancer cells. Herein, we review the mechanisms by which NK cells receive mechanical signals and explore recent key findings regarding the impact of the physical characteristics of solid tumors on NK cell functions. Data suggest that different mechanical stresses present in solid tumors facilitate NK cell functions, especially infiltration and degranulation. Moreover, we review recent engineering advances that can be used to systemically study the role of mechanical forces on NK cell activity. Understanding the mechanisms by which NK cells interpret their environment presents potential targets to enhance NK cell immunotherapies for the treatment of solid tumors.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) can occur due to maternal IgG antibodies targeting platelet antigens, causing life-threatening bleeding in the neonate. However, the disease manifests itself in only a fraction of pregnancies, most commonly with anti-HPA-1a antibodies. We found that in particular, the core fucosylation in the IgG-Fc tail is highly variable in anti-HPA-1a IgG, which strongly influences the binding to leukocyte IgG-Fc receptors IIIa/b (FcγRIIIa/b). Currently, gold-standard IgG-glycoanalytics rely on complicated methods (e.g., mass spectrometry (MS)) that are not suited for diagnostic purposes. Our aim was to provide a simplified method to quantify the biological activity of IgG antibodies targeting cells. We developed a cellular surface plasmon resonance imaging (cSPRi) technique based on FcγRIII-binding to IgG-opsonized cells and compared the results with MS. The strength of platelet binding to FcγR was monitored under flow using both WT FcγRIIIa (sensitive to Fc glycosylation status) and mutant FcγRIIIa-N162A (insensitive to Fc glycosylation status). The quality of the anti-HPA-1a glycosylation was monitored as the ratio of binding signals from the WT versus FcγRIIIa-N162A, using glycoengineered recombinant anti-platelet HPA-1a as a standard. The method was validated with 143 plasma samples with anti-HPA-1a antibodies analyzed by MS with known clinical outcomes and tested for validation of the method. The ratio of patient signal from the WT versus FcγRIIIa-N162A correlated with the fucosylation of the HPA-1a antibodies measured by MS (r=-0.52). Significantly, FNAIT disease severity based on Buchanan bleeding score was similarly discriminated against by MS and cSPRi. In conclusion, the use of IgG receptors, in this case, FcγRIIIa, on SPR chips can yield quantitative and qualitative information on platelet-bound anti-HPA-1a antibodies. Using opsonized cells in this manner circumvents the need for purification of specific antibodies and laborious MS analysis to obtain qualitative antibody traits such as IgG fucosylation, for which no clinical test is currently available.

Unsupervised anomaly detection (AD) is critical for a wide range of practical applications, from network security to health and medical tools. Due to the diversity of problems, no single algorithm has been found to be superior for all AD tasks. Choosing an algorithm, otherwise known as the Algorithm Selection Problem (ASP), has been extensively examined in supervised classification problems, through the use of meta-learning and AutoML, however, it has received little attention in unsupervised AD tasks. This research proposes a new meta-learning approach that identifies an appropriate unsupervised AD algorithm given a set of meta-features generated from the unlabelled input dataset. The performance of the proposed meta-learner is superior to the current state of the art solution. In addition, a mixed model statistical analysis has been conducted to examine the impact of the meta-learner components: the meta-model, meta-features, and the base set of AD algorithms, on the overall performance of the meta-learner. The analysis was conducted using more than 10,000 datasets, which is significantly larger than previous studies. Results indicate that a relatively small number of meta-features can be used to identify an appropriate AD algorithm, but the choice of a meta-model in the meta-learner has a considerable impact.

Introduction: Cerebral visual impairment (CVI) is the most common cause of visual impairment in children in the UK. Diagnosis is based on identification of visual behaviours (ViBes) relating to visual dysfunction. Examination techniques and inventories have been developed to elicit these in children with a developmental age of two years or more. The absence of a structured approach to recording visual behaviours in children with complex needs is a barrier to diagnosis. The aim of the study was to develop a matrix of visual behaviours seen in pre-verbal and pre-motor children with visual impairment and establish its content validity and inter-rater reliability. Methods ViBe content validation: Visual behaviour descriptors relating to visual function were collated and categorised by expert consensus of vision professionals into a matrix composed of three functions (attention, field/fixation, motor response) and five levels (0 = no awareness; 1 = visual awareness; 2 = visual attention; 3 = visual detection; 4 = visual understanding). ViBe inter-rater reliability: The participants (two orthoptists, an optometrist, an ophthalmologist and two qualified teachers of the visually impaired) used the ViBe matrix to independently score each of 17 short video clips of children demonstrating visual behaviours seen in CVI. Results: The ViBe matrix will be presented. Cohen’s kappa for the matrix was 0.67, demonstrating moderate-to-strong inter-rater reliability. Conclusion: The development of standardised descriptors can support clinicians and teachers in identifying areas of concern for children with complex needs. In addition, the ViBe matrix could be utilised in research, clinical and diagnostic reports to clearly communicate the areas of visual dysfunction and track progress resulting from interventions. Key Points • The absence of a structured approach to recording visual behaviours in children with complex needs is a barrier to diagnosis. • The ViBe matrix offers descriptors relating to visual behaviours and has demonstrated acceptable inter-rater reliability. • The tool may support the identification and diagnosis of cerebral visual impairment in a population of children who cannot access standard testing.

IntroductionGambling can have serious consequences for many aspects of a person’s life. Yet relatively few people with gambling problems seek help. This study examines the extent to which exclusion from casino venues among other factors may act as a motivator for further help-seeking among casino gamblers (both landbased and remote) with at-risk or disordered gambling behavior. In addition, the barriers that prevent gamblers from accepting help are examined.MethodsGamblers from Swiss casinos completed a written questionnaire twice, at 6-month intervals. The questions included whether they had sought help in the past 6 months.ResultsFor those with a SOGS-R rating of 1 or over (n = 173) at the second survey point, a difference in help-seeking was found between the excluded and non-excluded gamblers (p

Objectives Women of low socioeconomic status have been described as having suboptimal prenatal care, which in turn has been associated with poor pregnancy outcomes. Many types of conditional cash transfer (CCT) programmes have been developed, including programmes to improve prenatal care or smoking cessation during pregnancy, and their effects demonstrated. However, ethical critiques have included paternalism and lack of informed choice. Our objective was to determine if women and healthcare professionals (HPs) shared these concerns.Design Prospective qualitative research.Setting We included economically disadvantaged women, as defined by health insurance data, who participated in the French NAITRE randomised trial assessing a CCT programme during prenatal follow-up to improve pregnancy outcomes. The HP worked in some maternities participating in this trial.Participants 26 women, 14 who received CCT and 12 who did not, mostly unemployed (20/26), and - 7 HPs.Interventions We conducted a multicentre cross-sectional qualitative study among women and HPs who participated in the NAITRE Study to assess their views on CCT. The women were interviewed after childbirth.Results Women did not perceive CCT negatively. They did not mention feeling stigmatised. They described CCT as a significant source of aid for women with limited financial resources. HP described the CCT in less positive terms, for example, expressing concern about discussing cash transfer at their first medical consultation with women. Though they emphasised ethical concerns about the basis of the trial, they recognised the importance of evaluating CCT.Conclusions In France, a high-income country where prenatal follow-up is free, HPs were concerned that the CCT programme would change their relationship with patients and wondered if it was the best use of funding. However, women who received a cash incentive said they did not feel stigmatised and indicated that these payments helped them prepare for their baby’s birth.Trial registration number NCT02402855

The Sustainable Development Goals (SDGs) and their indicators provide opportunities to best combine the available knowledge and data to monitor and estimate different metrics and track their progress. The overall picture can be complex as some indicators are often interconnected (e.g., rural and/or urban development with a water body’s status). Two factors can play a crucial role in achieving the SDGs: the use of new technologies for database building and multidisciplinary studies and understanding. This study aims to explore these factors, highlight their importance and provide an example as guidance of their proper and combinative use. Ireland is used as an example of a data-scarce case with poor–slow progress, especially on the environmental SDGs. Two “non-reported” SDG indicators (lack of data) are selected and estimated in this work using freely available data (remote sensing, satellite imagery) and geospatial software for the first time in the country. The results show improvements in rural and urban development; however, this is accompanied by negative environmental consequences. A more holistic approach is needed and a broader conceptual model is presented to avoid any misleading interpretations of the study of SDGs. The transition to the modern technological and multidisciplinary evolution requires respective knowledge and understanding, strongly based on complex systems analysis.

Moving object path prediction in traffic scenes from the perspective of a moving vehicle can improve safety on the road, which is the aim of Advanced Driver Assistance Systems (ADAS). However, this task still remains a challenge. Work has been carried out on the use of x,y positional information of the moving objects only. However, besides positional information there is more information that surrounds a vehicle that can be leveraged in the prediction along with the x,y features. This is known as contextual information. In this work, a deep exploration of these features is carried out by evaluating different types of data, using different fusion strategies. The core architectures of this model are CNN and LSTM architectures. It is concluded that in the prediction task, not only are the features important, but the way they are fused in the developed architecture is also of importance.

In welchem Ausmaß schränkte der Lockdown im Frühling 2020 Frauen und Männer mit und ohne Kinder im Haushalt darin ein, danach zu streben, was jede*r sich wünscht (das gute Leben)? Die Auswertung einer Online-Befragung von rund 1 000 Personen einer Deutschschweizer Hochschule zeigt, dass Frauen mit Kindern stark eingeschränkt waren in der Gestaltung ihres guten Lebens. Im Vergleich zu Männern mit Kindern haben sich Frauen im nicht-repräsentativen Sample rund doppelt so oft in ihrer Arbeitskapazität eingeschränkt wegen zusätzlicher Betreuungsarbeiten. Frauen mit Kindern waren zudem stärker von negativen Auswirkungen des Lockdowns betroffen, so spürten sie am stärksten die Zunahme von Partnerschaftskonflikten und fühlten sich am wenigsten unterstützt vom privaten Umfeld. Daneben zeigt die Analyse unerwartete Geschlechtermuster: Männer mit Kindern berichten auch von Verhaltenseinschränkungen im Lockdown und häufiger von fehlender institutioneller Unterstützung. Es bedarf für die Schweiz generell einer besser ausgebauten Familienpolitik und gezielter Unterstützung bei der Kinderbetreuung im Fall eines Lockdowns.

Abstract Background Colony-stimulating factor 1 (CSF1) expression in the central nervous system (CNS) increases in response to a variety of stimuli, and CSF1 is overexpressed in many CNS diseases. In young adult mice, we previously showed that CSF1 overexpression in the CNS caused the proliferation of IBA1+ microglia without promoting the expression of M2 polarization markers. Methods Immunohistochemical and molecular analyses were performed to further examine the impact of CSF1 overexpression on glia in both young and aged mice. Results As CSF1 overexpressing mice age, IBA1+ cell numbers are constrained by a decline in proliferation rate. Compared to controls, there were no differences in expression of the M2 markers ARG1 and MRC1 (CD206) in CSF1 overexpressing mice of any age, indicating that even prolonged exposure to increased CSF1 does not impact M2 polarization status in vivo. Moreover, RNA-sequencing confirmed the lack of increased expression of markers of M2 polarization in microglia exposed to CSF1 overexpression but did reveal changes in expression of other immune-related genes. Although treatment with inhibitors of the CSF1 receptor, CSF1R, has been shown to impact other glia, no increased expression of oligodendrocyte lineage or astrocyte markers was observed in CSF1 overexpressing mice. Conclusions Our study indicates that microglia are the primary glial lineage impacted by CSF1 overexpression in the CNS and that microglia ultimately adapt to the presence of the CSF1 mitogenic signal.

Abstract Background Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on ‘rates-of-molecular yields’ in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively. Methods We discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. Results Significant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns. Conclusions Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

Abstract Background Medication errors have been identified as the most common preventable cause of adverse events. The lack of granularity in medication error terminology has led pharmacovigilance experts to rely on information in individual case safety reports’ (ICSRs) codes and narratives for signal detection, which is both time consuming and labour intensive. Thus, there is a need for complementary methods for the detection of medication errors from ICSRs. The aim of this study is to evaluate the utility of two natural language processing text mining methods as complementary tools to the traditional approach followed by pharmacovigilance experts for medication error signal detection. Methods The safety surveillance advisor (SSA) method, I2E text mining and University of Copenhagen Center for Protein Research (CPR) text mining, were evaluated for their ability to extract cases containing a type of medication error where patients extracted insulin from a prefilled pen or cartridge by a syringe. A total of 154,209 ICSRs were retrieved from Novo Nordisk’s safety database from January 1987 to February 2018. Each method was evaluated by recall (sensitivity) and precision (positive predictive value). Results We manually annotated 2533 ICSRs to investigate whether these contained the sought medication error. All these ICSRs were then analysed using the three methods. The recall was 90.4, 88.1 and 78.5% for the CPR text mining, the SSA method and the I2E text mining, respectively. Precision was low for all three methods ranging from 3.4% for the SSA method to 1.9 and 1.6% for the CPR and I2E text mining methods, respectively. Conclusions Text mining methods can, with advantage, be used for the detection of complex signals relying on information found in unstructured text (e.g., ICSR narratives) as standardised and both less labour-intensive and time-consuming methods compared to traditional pharmacovigilance methods. The employment of text mining in pharmacovigilance need not be limited to the surveillance of potential medication errors but can be used for the ongoing regulatory requests, e.g., obligations in risk management plans and may thus be utilised broadly for signal detection and ongoing surveillance activities.

Optimisation of tissue engineering (TE) processes requires models that can identify relationships between the parameters to be optimised and predict structural and performance outcomes from both physical and chemical processes. Currently, Design of Experiments (DoE) methods are commonly used for optimisation purposes in addition to playing an important role in statistical quality control and systematic randomisation for experiment planning. DoE is only used for the analysis and optimisation of quantitative data (i.e., number-based, countable or measurable), while it lacks the suitability for imaging and high dimensional data analysis. Machine learning (ML) offers considerable potential for data analysis, providing a greater flexibility in terms of data that can be used for optimisation and predictions. Its application within the fields of biomaterials and TE has recently been explored. This review presents the different types of DoE methodologies and the appropriate methods that have been used in TE applications. Next, ML algorithms that are widely used for optimisation and predictions are introduced and their advantages and disadvantages are presented. The use of different ML algorithms for TE applications is reviewed, with a particular focus on their use in optimising 3D bioprinting processes for tissue-engineered construct fabrication. Finally, the review discusses the future perspectives and presents the possibility of integrating DoE and ML in one system that would provide opportunities for researchers to achieve greater improvements in the TE field.

The COVID-19 pandemic has had an extensive impact on the global higher education sector. In a written survey, staff and students at the Lucerne School of Social Work reported how they had coped with the challenges to their teaching or respective learning situation. The initial survey was conducted during the lockdown in spring 2020, and the follow-up survey was performed in the period of relaxed sanitary measures in summer 2020. During the first wave of the survey, 51 employees and 225 students participated. In the follow-up survey, 28 employees and 117 students partook. Findings indicate that the increased workload created by the transition was stressful for both staff and students but overall was handled well. Staff and students who felt supported by the university management experienced less psychological distress. Since the outbreak of the pandemic, there has been an effort to develop hybrid forms of teaching. Because the social work curriculum contains building blocks that are difficult to implement in the form of distance learning, the transition posed challenges for both staff and students. During times of transition, university management must carefully assess the support needs of staff and students and take appropriate action.

Introduction: Hospitals commonly use Press Ganey (PG) patient satisfaction surveys for benchmarking physician performance. PG scores range from 1 to 5, with 5 being the highest, which is known as the “topbox” score. Our objective was to identify patient and physician factors associated with topbox PG scores in the emergency department (ED). Methods: We looked at PG surveys from January 2015–December 2017 at an academic, urban hospital with 78,000 ED visits each year. Outcomes were topbox scores for the questions: “Likelihood of your recommending our ED to others”; and “Courtesy of the doctor.” We analyzed topbox scores using generalized estimating equation models clustered by physician and adjusted for patient and physician factors. Patient factors included age, gender, race, ethnicity, and ED area where patient was seen. The ED has four areas based on patient acuity: emergent; urgent; vertical (urgent but able to sit in a recliner rather than a gurney); and fast track (non-urgent). Physician factors included age, gender, race, ethnicity, and number of years at current institution. Results: We analyzed a total of 3,038 surveys. For “Likelihood of your recommending our ED to others,” topbox scores were more likely with increasing patient age (odds ratio [OR] 1.07; 95% confidence interval [CI], 1.03–1.12); less likely among female compared to male patients (OR 0.81; 95% CI, 0.70–0.93); less likely among Asian compared to White patients (OR 0.71; 95% CI, 0.60–0.83); and less likely in the urgent (OR 0.71; 95% CI, 0.54–0.93) and vertical areas (OR 0.71; 95% CI 0.53–0.95) compared to fast track. For “Courtesy of the doctor,” topbox scores were more likely with increasing patient age (OR 1.1; CI, 1.06–1.14); less likely among Asian (OR 0.70; 95% CI, 0.58–0.84), Black (OR 0.66; 95% CI, 0.45–0.96), and Hispanic patients (OR 0.68; 95% CI, 0.55–0.83) compared to White patients; and less likely in urgent area (OR 0.69; 95% CI, 0.50–0.95) compared to fast track. Conclusion: Increasing patient age was associated with increased likelihood of topbox scores, while Asian patients, and urgent and vertical areas had decreased likelihood of topbox scores. We encourage hospitals that use PG topbox scores as financial incentives to understand the contribution of non-service factors to these scores.

Abstract Increasing exploitation of marine natural resources and expansion of energy infrastructure, shipping, and aquaculture across the oceans are placing increased pressure on marine life. Biodiversity offsets, as the last stage of the mitigation hierarchy, provide an opportunity to promote a more sustainable basis for development by addressing residual impacts and achieving “no net loss” for biodiversity. Despite debate around their effectiveness, biodiversity offsets are seeing increasing application on land but remain a rarely used tool in the marine environment. We assess how offsets can be applied in the marine environment to achieve better biodiversity outcomes, and identify implications for conservation policy and practice. For instance, spatial conservation planning provides opportunities to move away from a siloed, project‐by‐project, approach by pooling offsets on a regional scale. There are real differences between marine and terrestrial environments in relation to ecology, connectivity, data availability, management options, and impact perception, and marine offsets are therefore often regarded as challenging. However, fundamental offset principles, types, and approaches apply equally on land and at sea. Marine biodiversity offset approaches can build on the experience of terrestrial offsets but can also innovate to help achieve biodiversity gains and contribute toward global and national biodiversity targets.

Antibody dependent cellular cytotoxicity (ADCC) is an Fc-dependent effector function of IgG important for anti-viral immunity and anti-tumor therapies. NK-cell mediated ADCC is mainly triggered by IgG-subclasses IgG1 and IgG3 through the IgG-Fc-receptor (FcγR) IIIa. Polymorphisms in the immunoglobulin gamma heavy chain gene likely form a layer of variation in the strength of the ADCC-response, but this has never been studied in detail. We produced all 27 known IgG allotypes and assessed FcγRIIIa binding and ADCC activity. While all IgG1, IgG2, and IgG4 allotypes behaved similarly within subclass, large allotype-specific variation was found for IgG3. ADCC capacity was affected by residues 291, 292, and 296 in the CH2 domain through altered affinity or avidity for FcγRIIIa. Furthermore, allotypic variation in hinge length affected ADCC, likely through altered proximity at the immunological synapse. Thus, these functional differences between IgG allotypes have important implications for therapeutic applications and susceptibility to infectious-, allo- or auto-immune diseases.

Cartilage is an avascular tissue with extremely limited self-regeneration capabilities. At present, there are no existing treatments that effectively stop the deterioration of cartilage or reverse its effects; current treatments merely relieve its symptoms and surgical intervention is required when the condition aggravates. Thus, cartilage damage remains an ongoing challenge in orthopaedics with an urgent need for improved treatment options. In recent years, major advances have been made in the development of three-dimensional (3D) bioprinted constructs for cartilage repair applications. 3D bioprinting is an evolutionary additive manufacturing technique that enables the precisely controlled deposition of a combination of biomaterials, cells, and bioactive molecules, collectively known as bioink, layer-by-layer to produce constructs that simulate the structure and function of native cartilage tissue. This review provides an insight into the current developments in 3D bioprinting for cartilage tissue engineering. The bioink and construct properties required for successful application in cartilage repair applications are highlighted. Furthermore, the potential for translation of 3D bioprinted constructs to the clinic is discussed. Overall, 3D bioprinting demonstrates great potential as a novel technique for the fabrication of tissue engineered constructs for cartilage regeneration, with distinct advantages over conventional techniques.

The River Basin Management Plan (RBMP) is an essential component of the European Union Water Framework Directive that details an integrated approach required to protect, improve and sustainably manage water resources. RBMP were intended to be produced for the periods 2009–2015, 2016–2021 and 2022–2027. However, after two years of delays in the development processes, the Republic of Ireland produced its first RBMP in 2010. The second RBMP cycle was also implemented in 2018 and is expected to run until the end of 2021 to give way to the third RBMP, whose consultation processes have been ongoing since December 2019. This paper contributes to the forthcoming RBMP by assessing stakeholders’ perspectives on the second RBMP through a desk-based review and by conducting interviews with nine institutions (14 interviewees). The qualitatively analysed interviews reveal a broad spectrum of actors associated with water management and governance in the Republic of Ireland through a three-tier governance structure that has been delivered (with amendment) through the first two RBMPs. Organisations such as the An Fóram Uisce|The Water Forum, the Environmental Protection Agency, the Local Authority Waters, and the Agricultural Sustainability Support and Advisory Programme have responsibilities designated in the RBMPs to deliver improved water quality, integrated catchment management, community engagement and awareness-raising. Trust has also been building up among these organisations and other agencies in the water sector. Despite these responsibilities and progress made, the interviews identified communication lapses, ineffective collaboration and coordination among stakeholders and late implementation to be hampering the successful delivery of the second RBMP, in addition to significant pressures acting on water bodies from agricultural activities and urban wastewater treatment. Towards the third RBMP, the paper concludes that optimised water sector finance, enhanced and well-resourced communications, and improved stakeholder collaboration are needed to foster effective and efficient water services delivery and quality. More so, given the cross-cutting impact of the Sustainable Development Goals on water resources and the interconnected relations among the goals, the paper further recommends the integration of the SDGs in the various plans of actions and a co-benefits approach to derive the triple benefits from biodiversity, climate change initiatives and water quality measures.

The objective of our study was the alignment of microsatellite or simple sequence repeat (SSR) marker data across germplasm collections of cherry within Europe. Through the European Cooperative program for Plant Genetic Resources ECPGR, a number of European germplasm collections had previously been analysed using standard sets of SSR loci. However, until now these datasets remained unaligned. We used a combination of standard reference genotypes and ad-hoc selections to compile a central dataset representing as many alleles as possible from national datasets produced in France, Great Britain, Germany, Italy, Sweden and Switzerland. Through the comparison of alleles called in data from replicated samples we were able to create a series of alignment factors, supported across 448 different allele calls, that allowed us to align a dataset of 2241 SSR profiles from six countries. The proportion of allele comparisons that were either in agreement with the alignment factor or confounded by null alleles ranged from 67% to 100% and this was further improved by the inclusion of a series of allele-specific adjustments. The aligned dataset allowed us to identify groups of previously unknown matching accessions and to identify and resolve a number of errors in the prior datasets. The combined and aligned dataset represents a significant step forward in the co-ordinated management of field collections of cherry in Europe.

ObjectivesSixty-five per cent of older people have hypertension, but little is known about their preferences and concerns regarding hypertension management. Guidelines on hypertension lack consensus on how to treat older people without previous cardiovascular disease (CVD). This asks for explicit consideration of patient preferences in decision making. Therefore, the aim of this study was to explore older peoples’ experiences, preferences, concerns and perceived involvement regarding hypertension management.DesignQualitative interview study.SettingParticipants were selected from 11 general practitioner (GP) practices in the Netherlands and purposively sampled until data saturation was achieved. Semistructured interviews were conducted, audio recorded and analysed by two researchers using thematic analysis.ParticipantsFifteen community dwelling older people aged 74–93 years with hypertension and without previous CVD participated.ResultsInterviewees rarely started the conversation about hypertension management with their GP, although they did have concerns. Reasons for not discussing the subject included low priority of hypertension concerns, reliance on GPs or trust in GPs to make the right decision on their behalf. Also, interviewees anticipated regret of reducing medication, fearing vascular incidents. Interviewees would like to discuss tailoring treatment to their needs, deprescription of medication and ways to reduce side effects. They expected GPs to be more transparent on treatment effects.ConclusionOlder people describe having little involvement in hypertension management, although they have several concerns. Since GPs are also known to be hesitant to bring up this subject, we signal a conspiracy of silence about antihypertensive medication. Through breaking this silence, GPs can facilitate shared decision-making on hypertension management and better tailored care.

Cytoplasmic Actin Gamma 1 (ACTG1) gene variant are autosomal dominant and can cause CNS anomalies (Baraitser Winter Malformation Syndrome; BWMS). ACTG1 anomalies in offspring include agenesis of the corpus callosum (ACC) and neuronal heterotopia which are ectopic nodules of nerve cells that failed to migrate appropriately. Subcortical and periventricular neuronal heterotopia have been described previously in association with ACC. In this case report, we investigated a neonatal brain with an ACTG1 gene variant and a phenotype of ACC, and neuronal heterotopia (ACC-H) which was diagnosed on antenatal MR imaging and was consistent with band heterotopia seen on post-mortem brain images. Histologically clusters of neurons were seen in both the subcortical and periventricular white matter (PVWM) brain region that coincided with impaired abnormalities in glial formation. Immunohistochemistry was performed on paraffin-embedded brain tissue blocks from this case with ACTG1 variant and an age-matched control. Using tissue sections from the frontal lobe, we examined the distribution of neuronal cells (HuC/HuD, calretinin, and parvalbumin), growth cone (drebrin), and synaptic proteins (synaptophysin and SNAP-25). Additionally, we investigated how the ACTG1 variant altered astroglia (nestin, GFAP, vimentin); oligodendroglia (OLIG2) and microglia (Iba-1) in the corpus callosum, cortex, caudal ganglionic eminence, and PVWM. As predicted in the ACTG1 variant case, we found a lack of midline radial glia and glutamatergic fibers. We also found disturbances in the cortical region, in glial cells and a lack of extracellular matrix components in the ACTG1 variant. The caudal ganglionic eminence and the PVWM regions in the ACTG1 variant lacked several cellular components that were identified in a control case. Within the neuronal heterotopia, we found evidence of glutamatergic and GABAergic neurons with apparent synaptic connections. The data presented from this case study with BWMS with variants in the ACTG1 gene provides insight as to the composition of neuronal heterotopia, and how disturbances of important migratory signals may dramatically affect ongoing brain development.

The function of the low-affinity IgG-receptor FcγRIIIb (CD16b), which is uniquely and abundantly expressed on human granulocytes, is not clear. Unlike the other Fcγ receptors (FcγR), it is a glycophosphatidyl inositol (GPI) -anchored molecule and does not have intracellular signaling motifs. Nevertheless, FcγRIIIb can cooperate with other FcγR to promote phagocytosis of antibody-opsonized microbes by human neutrophils. Here we have investigated the role of FcγRIIIb during antibody-dependent cellular cytotoxicity (ADCC) by neutrophils toward solid cancer cells coated with either trastuzumab (anti-HER2) or cetuximab (anti-EGFR). Inhibiting FcγRIIIb using CD16-F(ab')2 blocking antibodies resulted in substantially enhanced ADCC. ADCC was completely dependent on FcγRIIa (CD32a) and the enhanced ADCC seen after FcγRIIIb blockade therefore suggested that FcγRIIIb was competing with FcγRIIa for IgG on the opsonized target cells. Interestingly, the function of neutrophil FcγRIIIb as a decoy receptor was further supported by using neutrophils from individuals with different gene copy numbers of FCGR3B causing different levels of surface FcγRIIIb expression. Individuals with one copy of FCGR3B showed higher levels of ADCC compared to those with two or more copies. Finally, we show that therapeutic antibodies intended to improve FcγRIIIa (CD16a)-dependent natural killer (NK) cell ADCC due to the lack of fucosylation on the N-linked glycan at position N297 of the IgG1 heavy chain Fc-region, show decreased ADCC as compared to regularly fucosylated antibodies. Together, these data confirm FcγRIIIb as a negative regulator of neutrophil ADCC toward tumor cells and a potential target for enhancing tumor cell destruction by neutrophils.

Source protection is part of a multi-solution approach for the provision of safe drinking water. In the Republic of Ireland, community-led Group Water Schemes (GWS) provide treated drinking water to approximately 69,000 rural households. Between 2009 and 2019, preliminary source protection assessments were undertaken for 70 GWS abstracting from surface water sources to provide physical catchment characterisation and untreated and treated water quality analysis. Catchment areas upstream of abstraction points varied in size, with 51.5% being less than 5 km2 and only 10.7% being larger than 100 km2. The majority (91%) of assessed GWS serve a population of less than 3000 people, and 94% supply less than 1500 m3 per day. Exceedances of the EU Drinking Water Regulations were recorded for 27 parameters, with the greatest number of exceedances due to total trihalomethanes followed by microbial contamination. The most frequent recommendation for improving GWS drinking water quality was associated with managing livestock access to local water bodies. Improving stakeholder engagement represented 38% of all recommendations made. Drinking water source protection measures and catchment-scale actions can be an additional model to assist in the delivery of Integrated Catchment Management and river basin management planning in the Republic of Ireland. For the GWS sector, challenges lie in securing resources to improve both source water and drinking water quality to deliver integrated catchment management plans for source protection.

Background: GPs are frequently confronted with patients with acute onset chest pain. Although usually benign, approximately 5% is due to acute coronary syndrome (ACS). Unfortunately, ACS is not always recognised, leading to a missed diagnosis in 2–5% of presentations. Aim: The authors set out to study the level of risk GPs are willing to accept with regards to missing an ACS diagnosis, and the receptiveness of implementing new clinical decision aids. Design & setting: This study involved an online survey among GPs in the Netherlands. Method: A concept survey was constructed, which was tested among a panel of 24 GPs. The survey was then modified to achieve content validity. This survey was electronically distributed among 1000 GPs. Results: A total of 313 (31.3%) GPs completed the survey. Of those surveyed, the median age was 50 years (interquartile range 41–57), 53.0% were female, and 6.4% were specialist GPs ('kaderarts') in cardiology or acute care. GPs estimated the missed ACS rate to be

Summary: Glioblastoma (GBM) is a lethal malignancy whose clinical intransigence has been linked to extensive intraclonal genetic and phenotypic diversity and the common emergence of therapeutic resistance. This interpretation embodies the implicit assumption that cancer stem cells or tumor-propagating cells are themselves genetically and functionally diverse. To test this, we screened primary GBM tumors by SNP array to identify copy number alterations (a minimum of three) that could be visualized in single cells by multicolor fluorescence in situ hybridization. Interrogation of neurosphere-derived cells (from four patients) and cells derived from secondary transplants of these same cells in NOD-SCID mice allowed us to infer the clonal and phylogenetic architectures. Whole-exome sequencing and single-cell genetic analysis in one case revealed a more complex clonal structure. This proof-of-principle experiment revealed that subclones in each GBM had variable regenerative or stem cell activity, and highlighted genetic alterations associated with more competitive propagating activity in vivo. : In this article, Greaves and colleagues show that tumor-propagating cells in glioblastoma are genetically and functionally heterogeneous. When used in in vivo experiments, these cells show a variable competitive capacity for tumor propagation and further genetic diversification, suggesting that glioblastoma evolves through complex dynamics of subclonal fitness advantage and acquisition of mutations and copy number alterations.

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Internationally, water management is moving from the traditional top-down approach to more integrated initiatives focussing on community-led action. With inadequacies in previous engagement initiatives undertaken through the first cycle of River Basin Management Planning for the EU Water Framework Directive (WFD), the Republic of Ireland has only recently embraced this bottom-up approach. The attempted introduction of national charging for domestic water use in 2015 has resulted in significant public disquiet and protest movements against the national government. In April 2015 we undertook a survey of current opinion on water management and community engagement initiatives in the Republic of Ireland and the United Kingdom. A total of 520 survey responses identified that although freshwater bodies are important in peoples' lives, respondents were typically unaware of global initiatives such as Integrated Water Resources Management and Integrated Catchment Management. Overall, 81% of respondents did not feel included in decisions about their water environment despite an overwhelming 95% believing that local communities should have a say in how the water environment is managed. However, only 35.1% of respondents stated that they would be willing to attend local water management engagement initiatives. Rather than supporting individual gain, respondents identified social gains for the local community as avenues for increasing local involvement in water initiatives. In the Republic of Ireland, a water engagement initiative that implements the national framework local delivery model should be developed and implemented. This would 1) contribute to the second round of WFD River Basin Management Planning; 2) facilitate stronger connections between local communities and their water environment; and 3) foster bottom-up initiatives that empower communities regarding local water management issues.

Understanding hydrological processes in large, open areas, such as catchments, and further modelling these processes are still open research questions. The system proposed in this work provides an automatic end-to-end pipeline from data collection to information extraction that can potentially assist hydrologists to better understand the hydrological processes using a data-driven approach. In this work, the performance of a low-cost off-the-shelf self contained sensor unit, which was originally designed and used to monitor liquid levels, such as AdBlue, fuel, lubricants etc., in a sealed tank environment, is first examined. This process validates that the sensor does provide accurate water level information for open water level monitoring tasks. Utilising the dataset collected from eight sensor units, an end-to-end pipeline of automating the data collection, data processing and information extraction processes is proposed. Within the pipeline, a data-driven anomaly detection method that automatically extracts rapid changes in measurement trends at a catchment scale. The lag-time of the test site (Dodder catchment Dublin, Ireland) is also analyzed. Subsequently, the water level response in the catchment due to storm events during the 27 month deployment period is illustrated. To support reproducible and collaborative research, the collected dataset and the source code of this work will be publicly available for research purposes.

Abstract (E): Chats perchés (2004) presents itself as a digression on an amusing piece of graffiti, arambling through Paris with recent political demonstrations in mind. Yet, Marker's film also leads oneto think about urban nomadism and suggests the possibility of a cinema of the territory.Abstract (F): Chats perchés (2004) se présente comme une digression autour d'un graffiti amusant etcomme une divagation parisienne qui se souvient des manifestations politiques récentes. Mais le filmde Marker ouvre aussi à la pensée d'un nomadisme urbain et suggère la possibilité d'un cinémadu territoire.

Periodontitis is a progressive disease of the periodontium with a complex, polymicrobial etiology. Recent Next-Generation Sequencing (NGS) studies of the microbial diversity associated with periodontitis have revealed strong, community-level differences in bacterial assemblages associated with healthy or diseased periodontal sites. In this study, we used NGS approaches to characterize changes in periodontal pocket bacterial diversity after standard periodontal treatment. Despite consistent changes in the abundance of certain taxa in individuals whose condition improved with treatment, post-treatment samples retained the highest similarity to pre-treatment samples from the same individual. Deeper phylogenetic analysis of periodontal pathogen-containing genera Prevotella and Fusobacterium found both unexpected diversity and differential treatment response among species. Our results highlight how understanding interpersonal variability among microbiomes is necessary for determining how polymicrobial diseases respond to treatment and disturbance.

Disclosure of financial conflicts of interest (COI) is intended to help reviewers assess the impact of potential bias on the validity of research results; however, there have been no empiric assessments of how reviewers understand and use disclosures in article evaluation. We investigate reviewers' perceptions of potential bias introduced by particular author disclosures, and whether reviewer characteristics are associated with a greater likelihood of perceiving bias.Of the 911 active reviewers from the Annals of Emergency Medicine, 410 were randomly selected and invited to complete our web-based, 3-part survey. We completed descriptive analysis of all survey responses and compared those responses across reviewer characteristics using 2 × 2 analyses and the Fisher exact test. We had a response rate of 54%. The majority of reviewers surveyed reported a high level of skepticism regarding financial relationships between authors and industry without a clear or consistent translation of that skepticism into the self-reported actions that characterize manuscript assessment. Only 13% of respondents believed physician consultants authoring articles based on company data are likely to have unlimited data access. 54% believed that bias most likely exists with any honorarium, regardless of monetary amount. Between 46% and 64%, depending on the type of financial relationship disclosed, reported that their recommendation for publication remains unchanged. Respondents reporting personal financial ties to industry were less likely to perceive bias in industry relationships and less likely to believe that bias exists with any monetary amount of honoraria.We recommend that the monetary amount of all financial relationships be reported with manuscript submissions, lead authors certify that they have unrestricted access to data, and reviewers disclose any financial ties to industry whether or not they are related to the manuscript under review. Further research is required to better understand reviewers' perceptions of financial relationships between authors and industry in order to develop clear and consistent guidelines for incorporating the perception of potential bias into manuscript assessments.