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Aims: The authors share their early experiences of developing and implementing a telehealth service for patients with chronic obstructive pulmonary disease (COPD), through a collaborative approach. The article will explore the process of implementing telehealth service in a local care community team, identifying opportunities for improving care delivery and person-centred care. Discussion: The initial feedback and thoughts of both patients and healthcare professionals were obtained. Such feedback included patient’s health insights, which helped improve risk assessment and personalised parameter settings. Conclusions: To-date, there has been a lack of robust evidence for the clinical benefits of telehealth. However, the feedback from staff and patients using telehealth was positive in several areas. Person-centred care plans also helped provide greater insight into patient’s health goals, thereby streamlining care.

The Met Office in the United Kingdom has developed a completely new probabilistic postprocessing system called IMPROVER to operate on outputs from its operational numerical weather prediction (NWP) forecasts and precipitation nowcasts. The aim is to improve weather forecast information to the public and other stakeholders while better exploiting the current and future generations of underpinning kilometer-scale NWP ensembles. We wish to provide seamless forecasts from nowcasting to medium range, provide consistency between gridded and site-specific forecasts, and be able to verify every stage of the processing. The software is written in a modern modular framework that is easy to maintain, develop, and share. IMPROVER allows forecast information to be provided with greater spatial and temporal detail and a faster update frequency than previous postprocessing. Independent probabilistic processing chains are constructed for each meteorological variable consisting of a series of processing stages that operate on predefined grids and blend outputs from several NWP inputs to give a frequently updated, probabilistic forecast solution. Probabilistic information is produced as standard, with the option of extracting a most likely or yes–no outcome if required. Verification can be performed at all stages, although it is only currently switched on for the most significant stages when run in real time. IMPROVER has been producing real-time output since March 2021 and became operational in spring 2022.

Childhood steroid-sensitive nephrotic syndrome is a frequently relapsing disease with significant short- and long-term complications, leading to high healthcare costs and reduced quality of life for patients. The majority of relapses are triggered by upper respiratory tract infections (URTIs) and evidence shows that daily low-dose prednisolone at the time of infection may reduce the risk of relapse.The aim of this study was to assess the cost effectiveness of a 6-day course of low-dose prednisolone at the start of a URTI when compared with placebo.A state-transition Markov model was developed to conduct a cost-utility analysis with the outcome measured in quality-adjusted life-years (QALYs). Resource use and outcome data were derived from the PREDNOS2 trial. The analysis was performed from a UK National Health Service perspective and the results were extrapolated to adulthood. Model parameter and structural uncertainty were assessed using sensitivity analyses.The base-case results showed that administering low-dose prednisolone at the time of a URTI generated more QALYs and a lower mean cost at 1 year compared with placebo. In the long-term, low-dose prednisolone was associated with a cost saving (£176) and increased effectiveness (0.01 QALYs) compared with placebo and thus remained the dominant treatment option. These findings were robust to all sensitivity analyses.A 6-day course of low-dose prednisolone at the time of a URTI in children with steroid-sensitive nephrotic syndrome has the potential to reduce healthcare costs and improve quality of life compared with placebo.

Although guidelines can reduce postoperative opioid prescription, the problem of unused opioids persists. We assessed the pattern of opioid prescription and utilization after total hip arthroplasty (THA) and total knee arthroplasty (TKA). We hypothesized that opioid prescription patterns can influence opioid utilization.With institutional ethics approval, patients undergoing THA and TKA were enrolled prospectively. Surveys on opioid use were completed at two, six, and 12 weeks after surgery. Patients' age, sex, American Society of Anesthesiologists' Physical Status score, first 24-hr opioid consumption, quantity of opioid prescribed, and quantity of opioid utilized were analyzed to evaluate their effect on opioid consumption, unused opioid, and patient satisfaction.Patients received prescriptions ranging from 200 morphine milligram equivalents (MME) to 800 MME. Three hundred and thirty THA and 230 TKA patients completed the surveys. Opioid utilization was influenced by the amount of prescribed opioids for both THA and TKA. The percentage of prescribed opioids used (~55% in THA and ~75% in TKA) and the proportion of patients using all prescribed opioids (~22% in THA and ~50% in TKA) were higher after TKA vs THA (P0.001 for both). Patients who used opioids for two days or less accounted for most (~50%) of the unused opioid. Patient satisfaction remained high and was not influenced by the amount of prescribed opioid.This study showed that larger prescriptions are associated with higher opioid consumption. A wide variation in opioid consumption requires approaches to minimize the initial opioid prescription and to provide additional prescriptions for patients that require higher levels of analgesia.RéSUMé: OBJECTIF: Bien que les lignes directrices puissent réduire la prescription d’opioïdes postopératoires, le problème des opioïdes inutilisés persiste. Nous avons évalué les schémas de prescription et d’utilisation d’opioïdes après une arthroplastie totale de la hanche (ATH) et une arthroplastie totale du genou (ATG). Nous avons émis l’hypothèse que les schémas de prescription d’opioïdes pouvaient influencer l’utilisation des opioïdes. MéTHODE: Avec l’approbation du comité d’éthique de notre établissement, les patients bénéficiant d’une ATH et une ATG ont été recrutés de manière prospective. Les questionnaires sur la consommation d’opioïdes ont été complétés deux, six et 12 semaines après la chirurgie. L’âge, le sexe et le score de statut physique selon l’American Society of Anesthesiologists des patients, ainsi que la consommation d’opioïdes au cours des premières 24 heures postopératoires, la quantité d’opioïdes prescrits et la quantité d’opioïdes utilisés ont été analysés pour évaluer leur effet sur la consommation d’opioïdes, les opioïdes inutilisés et la satisfaction des patients. RéSULTATS: Les patients ont reçu des ordonnances allant de 200 équivalents de morphine en milligrammes (EMM) à 800 EMM. Trois cent trente patients bénéficiant d’une ATH et 230 patients d’une ATG ont répondu aux questionnaires. L’utilisation des opioïdes a été influencée par la quantité d’opioïdes prescrits pour l’ATH et l’ATG. Le pourcentage d’opioïdes prescrits utilisés (~55 % dans l’ATH et ~75 % dans l’ATG) et la proportion de patients utilisant tous les opioïdes prescrits (~22 % dans l’ATH et ~50 % dans l’ATG) étaient plus élevés après l’ATG vs l’ATH (P0,001 pour les deux). Les patients qui ont utilisé des opioïdes pendant deux jours ou moins étaient à l’origine de la plupart (~ 50%) des opioïdes inutilisés. La satisfaction des patients est demeurée élevée et n’a pas été influencée par la quantité d’opioïdes prescrits. CONCLUSION: Cette étude a démontré que les ordonnances plus élevées sont associées à une consommation plus élevée d’opioïdes. Une grande variation dans la consommation d’opioïdes nécessite des approches visant à minimiser la prescription initiale d’opioïdes et à fournir des ordonnances supplémentaires aux patients qui nécessitent des niveaux plus élevés d’analgésie.

Published online: 06 Oct 2021. Purpose: The Australian English Communicative Development Inventory (OZI) is a 558-item parent report tool for assessing language development at 12–30 months. Here, we introduce the short form (OZI-SF), a 100-item, picture-supported, online instrument with substantially lower time and literacy demands. Method: In tool development (Study 1), 95 items were drawn from the OZI to match its item distribution by age of acquisition and semantic categories. Five items were added from four other semantic categories, plus 12 gestures and six games/routines. Simulations computed OZI-SF scores from existing long-form OZI norm data, and OZI and projected OZI-SF scores were correlated. In an independent norming sample (Study 2), parents (n¼230) completed the OZI-SF for their children aged 12–30 months. Child scores were analysed by age and sex. Result: OZI-SF and OZI scores correlate highly across age and language development levels. Vocabulary scores (receptive, expressive) correlate with age and the median for girls is higher until 24 months. By 24 months, 50% of the sample combine words “often”. The median time to OZI-SF completion was 12 minutes. Conclusion: Fitted percentiles permit working guidelines for typical (median) performance and lower cut-offs for children who may be behind on age-based expectations and/or at risk for a communication difficulty. The OZI-SF is a short-form of the OZI that has promise for research and clinical/educational use with Australian families. This work was supported by the Australian Research Council Centre of Excellence for the Dynamics of Language (ARC CoEDL, CE140100041).

Credited with averting almost 68% of new cases between 2000 and 2015, insecticide-treated bednets (ITNs) are one of the most efficacious malaria-prevention tools. Their effectiveness, however, depends on if and how they are used, making 'compliance' (and the social factors affecting it) a key area of interest for research on malaria transmission. This article situates the notion of compliance with 'bednet use' within everyday practices in an area of south-west Burkina Faso with high malaria transmission. By drawing on ethnographic fieldwork conducted between 2017 and 2018, it critically describes the precarious micro-environments that foreground bednet use-from gender and age to the means of (re)production of social and labour conditions-and assesses the bednets' effectiveness and community uptake. Bednet use stems from concrete, ordinary dynamics that interweave only apparently at the margins of the time individuals most need to be protected by a net. This work conceptualises 'compliance' beyond binary indicators of intervention uptake and locates 'use' as the result of contingent assemblages.

Aims Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort. Methods and results Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children ( Conclusion In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications.

Highlights • Dose escalation to MRI-defined prostate lesions using SABR is feasible and safe. • After an extended follow up, rates of Grade 2 + GU and GI toxicities were low. • No biochemical relapse was observed. • 10 minor dose variations were reported out of 80 ideal dose constraints., Introduction Dose escalation to dominant intraprostatic lesions (DILs) is a novel method to increase the therapeutic ratio in localised prostate cancer. The Stereotactic Prostate Augmented Radiotherapy with Cyberknife (SPARC) trial was designed to determine the feasibility of a focal boost defined with multiparametric magnetic resonance imaging (mpMRI) using stereotactic ablative body radiotherapy (SABR). Materials and methods Patients were included with newly diagnosed intermediate to high risk prostate cancer with at least one of: Gleason score 4 + 3, stage T3a, or PSA > 20 ng/ml. Visible disease on mpMRI was mandatory and up to 2 separate nodules were allowed. All patients received androgen deprivation. Patients received 36.25 Gy in 5 fractions using CyberKnife® and the DIL received a simultaneous boost to a maximum of 47.5 Gy, as allowed by OAR constraints. Genitourinary (GU) and gastrointestinal (GI) toxicity was reported using the RTOG scoring criteria. International Index of Erectile Function (IIEF) and EQ-5D global health scores were regularly captured. Results An interim safety analysis was performed on the first 8 patients, recruited between July 2013 and December 2015. Median follow up was 56 months (range 50–74). Median D95 values for the prostate PTV and boost volume were 36.55 Gy (range 35.87–36.99) and 46.62 Gy (range 44.85–48.25) respectively. Of the dose constraints, 10/80 were not achieved but all were minor dose variations. Grade 2+ acute GU and GI toxicities were 37.5% respectively while grade 2+ late GU and GI toxicities were 12.5% and 0% respectively. IIEF and quality of life scores recovered over time and all patients remain in biochemical remission. Conclusion The first patients have been successfully treated with prostate SABR and focal boost on the SPARC trial, with excellent adherence to the planning protocol. Toxicity and efficacy results are promising and further recruitment is underway.

Many Aboriginal and Torres Strait Islander children are affected by chronic middle ear infection or otitis media from infancy that has a negative impact on development of listening and communicatio...

This article is the fourth in a series introducing the reader to methods and theories relevant to advancing socio‐legal research. They are written for the curious rather than the expert reader and provide illustrations of how the theories, methods, and frameworks have been employed and might be used in your work. This article explores the use of case biography methods for socio‐legal studies. Drawing on ‘paths to justice’ studies, network analysis, and legal archaeology, we develop a case study of AC v.Berkshire West Primary Care Trust. We show how the judicial determination of the case suppressed a transgender rights narrative construction of the dispute in favour of one about health care law. Our case biography analysis explores how competing narratives can be traced not only through legal argument and literature, but also through the personnel involved, in ways that are obscured by formal records. Paying attention to biographical features leads to a richer understanding of cases, including the importance of pre‐ and post‐judicial decision‐making aspects.

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications., Graphical abstract

Aims and Objectives Neonatal inpatient care is reliant on experienced nursing care, yet little is known about how Kenyan hospitals foster the development of newborn nursing experience in newborn units. Design A Qualitative ethnographic design. Methods Face to face 29 in depth interviews were conducted with nurses providing neonatal care in one private, one faith based and one public hospital in Nairobi, Kenya between January 2017 and March 2018. All data were transcribed verbatim, coded in the original language and analysed using a framework approach. Results Across the sectors, nurses perceived experience as important to the provision of quality care. They noted that hospitals could foster experience through recruitment, orientation, continuous learning and retention. However, while the private hospital facilitated experience building the public and faith‐based hospitals experienced challenges due to human resource management practices and nursing shortages. Conclusion Health sector context influenced how experience was developed among nurses. Implications Nurturing experience will require that different health sectors adopt better recruitment for people interested in NBU work, better orientation and fewer rotations even without specialist nurse training.

Purpose: Research on fiscal implications of the bundled care (BC) model exist; however, patient-perceived experiences are less well known. As BC expands in Ontario, this study aims to examine these experiences with physiotherapy care within the total knee replacement (TKR) BC program. Methods: Qualitative cross-sectional study design. Semi-structured one-on-one telephone interviews were conducted with eight patients four to six weeks post-TKR. Thematic analysis was used. Results: This exploratory study identified three themes across the care journey that patients perceived as influencing their physiotherapy experiences: timely access to physiotherapy care, quality of physiotherapy care, and patient outcomes. Communication, clinical support, and social support were sub-themes. Conclusions: Patients’ overall experiences with BC physiotherapy were positive. Areas for improvement included coordination of postoperative physiotherapy and return-to-work support. Patients valued group settings and were interested in meeting previous TKR patients. Health system planners are advised to consider incorporating patient experiences when evaluating and developing BC programs to achieve patient-centred outcomes.

The epidemic that was a result of the Coronavirus (Cupples, 2019) began in China towards the end of 2019 and has quickly spread throughout the world. To minimize the spread of the virus and keep it as contained as possible, many countries have required residents to quarantine. This epidemic has been a major concern for students of all ages, especially college students. Students that attend universities have been affected more profoundly due to the close quarters of dorms, fraternities, sororities, and close classroom contact. Due to the contagiousness of the virus and the fact that many who are positive can be asymptomatic hundreds can be affected quickly. The pandemic has forced many students to quarantine themselves. This requires that they not leave their homes, rooms, and apartment for a period of up to 14 days. The purpose of this research was to assess how COVID has affected college students and how it has affected their eating habits and lifestyle habits.

Key Points Question In children with relapsing corticosteroid-sensitive nephrotic syndrome, does daily low-dose corticosteroid given at the time of upper respiratory tract infection prevent upper respiratory tract infection–related relapse? Findings In this randomized clinical trial of 365 children, daily low-dose corticosteroid therapy resulted in no difference in the frequency of upper respiratory tract infection–related relapses compared with placebo. Meaning Results of this study suggest that low-dose corticosteroid treatment is not beneficial as a strategy to prevent upper respiratory tract infection–related relapses., Importance In children with corticosteroid-sensitive nephrotic syndrome, many relapses are triggered by upper respiratory tract infections. Four small studies found that administration of daily low-dose prednisolone for 5 to 7 days at the time of an upper respiratory tract infection reduced the risk of relapse, but the generalizability of their findings is limited by location of the studies and selection of study population. Objective To investigate the use of daily low-dose prednisolone for the treatment of upper respiratory tract infection–related relapses. Design, Setting, and Participants This double-blind, placebo-controlled randomized clinical trial (Prednisolone in Nephrotic Syndrome [PREDNOS] 2) evaluated 365 children with relapsing steroid-sensitive nephrotic syndrome with and without background immunosuppressive treatment at 122 pediatric departments in the UK from February 1, 2013, to January 31, 2020. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020. Interventions At the start of an upper respiratory tract infection, children received 6 days of prednisolone, 15 mg/m2 daily, or matching placebo preparation. Those already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 daily or their alternate-day dose, whichever was greater. Main Outcomes and Measures The primary outcome was the incidence of first upper respiratory tract infection–related relapse. Secondary outcomes included overall rate of relapse, changes in background immunosuppressive treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, and quality of life. Results The modified intention-to-treat analysis population comprised 271 children (mean [SD] age, 7.6 [3.5] years; 174 [64.2%] male), with 134 in the prednisolone arm and 137 in the placebo arm. The number of patients experiencing an upper respiratory tract infection–related relapse was 56 of 131 (42.7%) in the prednisolone arm and 58 of 131 (44.3%) in the placebo arm (adjusted risk difference, −0.02; 95% CI, −0.14 to 0.10; P = .70). No evidence was found that the treatment effect differed according to background immunosuppressive treatment. No significant differences were found in secondary outcomes between the treatment arms. A post hoc subgroup analysis assessing the primary outcome in 54 children of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs 208 children of other ethnicity (risk ratio, 1.11; 95% CI, 0.81-1.54) found no difference in efficacy of intervention in those of South Asian ethnicity (test for interaction P = .09). Conclusions and Relevance The results of PREDNOS 2 suggest that administering 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of nephrotic syndrome in children in the UK. Further work is needed to investigate interethnic differences in treatment response. Trial Registration isrctn.org Identifier: ISRCTN10900733; EudraCT 2012-003476-39, This randomized clinical trial investigates whether a low daily dose of prednisolone in children with relapsing steroid-sensitive nephrotic syndrome prevents upper respiratory tract infection–related relapse.

BACKGROUND Characterising older adult engagement is important to determine the effectiveness of interventions. Engagement is the occupying of oneself in external stimuli and is observable across multiple dimensions of behaviour. Engagement of older adults is commonly investigated on a single behavioural dimension. OBJECTIVE In this article, we present a multidisciplinary approach for measuring and characterising engagement of older adults using techniques appropriate for people with varying degrees of dementia. METHODS Contexts for engagement included a dyadic reminiscence therapy interview and a 12-week technology driven group reminiscence therapy. Participants were older adults (8 female, 1 male, mean age: 79) who attended a day respite facility. Audio-visual recordings of the sessions were processed to analyse facial movement, lexical use, and prosodic patterns of speech. Facial movement was processed using OpenFace to measure the presence and intensity of facial movement. Lexical use was processed using the Linguistic Enquiry and Word Count to measure personal pronoun use, affective word use, and emotional tone of words in speech. Prosodic patterns of speech were processed using custom scripts written in Praat and Python, to measure mean duration of utterances, mean words per utterance, articulation rate and variability of F0. Mixed-effects modelling was used to assess effects of treatment conditions on dependent variable outcomes. RESULTS Results indicate measuring engagement through a multidimensional approach can sensitively capture older adults’ engagement. CONCLUSIONS Application of this method can enhance a researcher’s ability to measure older adult engagement, provide means to compare across interventions and contextual environments, and further develop the science of psychosocial intervention research.

Aims: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. Methods and results: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n=187 (62.1%)], underlying aetiology was non-syndromic (n=138, 45.6%), RASopathy (n=101, 33.6%), or inborn error of metabolism (IEM) (n=49, 16.3%). The most common reasons for presentation were symptoms (n=77, 29.3%), which were more prevalent in those with syndromic disease (n=62, 61.4%, P&nbsp

Background Undernourished children in low- and middle-income countries remain at elevated risk of death following hospital discharge, even when treated during hospitalisation using World Health Organisation recommended guidelines. The role of community health workers (CHWs) in supporting post-discharge recovery to improve outcomes has not been adequately explored. Methods This paper draws on qualitative research conducted as part of the Childhood Acute Illnesses and Nutrition (CHAIN) Network in Bangladesh and Kenya. We interviewed family members of 64 acutely ill children admitted across four hospitals (a rural and urban hospital in each country). 27 children had severe wasting or kwashiorkor on admission. Family members were interviewed in their homes soon after discharge, and up to three further times over the following six to fourteen months. These data were supplemented by observations in facilities and homes, key informant interviews with CHWs and policy makers, and a review of relevant guidelines. Results Guidelines suggest that CHWs could play a role in supporting recovery of undernourished children post-discharge, but the mechanisms to link CHWs into post-discharge support processes are not specified. Few families we interviewed reported any interactions with CHWs post-discharge, especially in Kenya, despite our data suggesting that opportunities for CHWs to assist families post-discharge include providing context sensitive information and education, identification of danger signs, and supporting linkages with community-based services and interventions. Although CHWs are generally present in communities, challenges they face in conducting their roles include unmanageable workloads, few incentives, lack of equipment and supplies and inadequate support from supervisors and some community members. Conclusion A multi-pronged approach before or on discharge is needed to strengthen linkages between CHWs and children vulnerable to poor outcomes, supported by clear guidance. To encourage scale-ability and cost-effectiveness of interventions, the most vulnerable, high-risk children, should be targeted, including undernourished children. Intervention designs must also take into account existing health worker shortages and training levels, including for CHWs, and how any new tasks or personnel are incorporated into hospital and broader health system hierarchies and systems. Any such interventions will need to be evaluated in carefully designed studies, including tracking for unintended consequences.

In order to meet the unique needs of local populations, health and care providers need to come together as a collective. A model of integration in line with the NHS Long Term Plan will support transformation, sustainability and meeting the increasing demands on the NHS. Due the complexity and variety of services in care communities, it is vital that organisations and the third sector acknowledge and understand one another with greater depth. Primary care networks (PCNs) support this by dissolving organisational boundaries, with services wrapping around each other and moving forward as one system. This article describes how one PCN in Wirral committed to appreciating each service's roles. By engaging regularly in different ways, members of the PCN were able build on professional relationships. The refocusing and reconnecting regularly as a collective team enabled a more streamlined approach to proactive, place-based patient care while providing professionals with improved working relationships, skill-sharing and increased job satisfaction.

The tumor microenvironment plays a critical role in the proliferation and chemoresistance of cancer cells. Growth factors (GFs) are known to interact with the extracellular matrix (ECM) via heparin binding sites, and these associations influence cell behavior. In the present study, we demonstrate the ability to define signals presented by the scaffold by pre-mixing growth factors, such as epidermal growth factor, into the heparin-based (HP-B) hydrogel prior to gelation. In the 3D biomimetic microenvironment, breast cancer cells formed spheroids within 24 hours of initial seeding. Despite higher number of proliferating cells in 2D cultures, 3D spheroids exhibited a higher degree of chemoresistance after 72 hours. Further, our RNA sequencing results highlighted the phenotypic changes influenced by solid-phase GF presentation. Wnt/beta-catenin and TGF-beta signaling were upregulated in the cells grown in the hydrogel, while apoptosis, IL2-STAT5 and PI3K-AKT-mTOR signaling were downregulated. With emerging technologies for precision medicine in cancer, this nature of fine-tuning the microenvironment is paramount for cultivation and downstream characterization of primary cancer cells and rare circulating tumor cells (CTCs), and effective screening of chemotherapeutic agents. National Institute of General Medical Sciences of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R35GM133610] We would like to thank Carla Finkielstein for her thoughtful discussions on experimental design and RNA seq data analysis. Research reported in this publication was supported by The National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM133610.

Continuing professional learning is vital to early childhood professionals, and the use of digital technology can potentially reduce costs and improve access. In this study, 74 educators across 17 early childhood services in Australian urban and regional locations completed a questionnaire about their personal and professional uses of digital technology to find resources. The results indicate most early childhood educators use digital technology to construct their own professional knowledge bases, and though they make some use of formal resources around national standards, they make greater use of informal resources and discussion groups. They tend to seek practical information and activity ideas and ways to connect with other professionals, although this varies somewhat by years of professional experience, age and the socioeconomic context they work in. Results highlight early childhood educators’ professional learning desires and the potential value of mobile learning for providing access to professional learning for early childhood educators working in resource-limited and geographically limited settings.

Electric fields are generated in vivo in a variety of physiologic and pathologic settings, including wound healing and immune response to injuries to epithelial barriers (e.g. lung pneumocytes). Immune cells are known to migrate towards both chemical (chemotaxis), physical (mechanotaxis) and electric stimuli (electrotaxis). Electrotaxis is the guided migration of cells along electric fields, and has previously been reported in T-cells and cancer cells. However, there remains a need for engineering tools with high spatial and temporal resolution to quantify EF guided migration. Here we report the development of an electrotaxis-on-chip (ETOC) platform that enables the quantification of dHL-60 cell, a model neutrophil-like cell line, migration toward both electrical and chemoattractant gradients. Neutrophils are the most abundant white blood cells and set the stage for the magnitude of the immune response. Therefore, developing engineering tools to direct neutrophil migration patterns has applications in both infectious disease and inflammatory disorders. The ETOC developed in this study has embedded electrodes and four migration zones connected to a central cell-loading chamber with migration channels [10 mu m X 10 mu m]. This device enables both parallel and competing chemoattractant and electric fields. We use our novel ETOC platform to investigate dHL-60 cell migration in three biologically relevant conditions: 1) in a DC electric field; 2) parallel chemical gradient and electric fields; and 3) perpendicular chemical gradient and electric field. In this study we used differentiated leukemia cancer cells (dHL60 cells), an accepted model for human peripheral blood neutrophils. We first quantified effects of electric field intensities (0.4V/cm-1V/cm) on dHL-60 cell electrotaxis. Our results show optimal migration at 0.6 V/cm. In the second scenario, we tested whether it was possible to increase dHL-60 cell migration to a bacterial signal [N-formylated peptides (fMLP)] by adding a parallel electric field. Our results show that there was significant increase (6-fold increase) in dHL60 migration toward fMLP and cathode of DC electric field (0.6V/cm, n=4, p-value

Systematic reviews show that clinical decision support systems (CDSSs) can improve the quality of clinical decisions and healthcare processes[1][1] and patient outcomes[2][2]; although caution has been expressed as to balancing the risks of using CDSSs (eg, alert fatigue) when only small or moderate

Supplemental Digital Content is available in the text., Background: Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs. Methods: Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used. Results: Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P=0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+-handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca2+-channels, and K+-channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P

Acute malnutrition in infants under 6 months (u6m) is increasingly recognised as a global public health problem. The World Health Organisation (WHO) guidelines for inpatient nutritional rehabilitation of infants u6m is re‐lactation: the re‐establishment of exclusive breastfeeding. Evidence suggests these guidelines are rarely followed in many low‐income settings. Two studies of infant nutritional rehabilitation undertaken in three public hospitals in coastal Kenya employed breastfeeding peer supporters (BFPSs) to facilitate WHO guideline implementation. To explore the acceptability of the strategy to health workers (HWs) and the BFPSs, in‐depth interviews were conducted with 20 HWs and five BFPSs in the three study hospitals. The HWs reported that the presence of the BFPSs changed the way infant nutritional rehabilitation was managed, increasing efforts at relactation and decreasing reliance on supplemental milk. BFPSs were said to help address staff shortages and had dedicated time to support and assist the mothers. Key to the success of the BFPSs was the social relationships they were able to establish with the mothers due to the similarity in their experiences and backgrounds. Despite the success of the BFPSs, human resource management and infrastructure challenges remained. BFPSs can successfully be employed to facilitate the implementation of the WHO guidelines for the nutritional rehabilitation of acutely malnourished infants u6m in hospitals in Kenya, establishing supportive social relationships and trust with the mothers of the acutely malnourished infants and helping to address the issue of human resource shortages.

The southwest monsoon rains in 2019 were the heaviest over India in a quarter of a century. The 2019 seasonal JJAS precipitation over the whole country was 110 % of its long period average (LPA) of 880mm. Precipitation is a cumulative field driven by many atmospheric processes both within nature and numerical prediction. It’s a weather variable that impacts everyone’s life and hence is used routinely to assess the skill of modelling systems. In this study, we have analyzed the 2019 JJAS seasonal precipitation forecast skill of two global ensemble models: (1) the UK Met Office GloSea5 and (2) the National Center for Medium Range Weather Forecasting (NCMRWF) Global Ensemble Prediction System (NEPS-G). The Integrated Multi-satellite Retrievals for Global Precipitation Measurement (IMERG-GPM) rainfall and ERA5 winds with high spatial resolution and temporal data are used for verification of the model forecasts across a seamless range of time scales. In order to compare a seamless range of time scales, we have summed forecast fields over time windows of forecast lead time from 1 day to 2 weeks. We also computed the actual skill and potential skill of the model ensemble forecasts at different lead windows. Our results for both models show large precipitation biases and reduced precipitation skills with forecast lead windows. We also found that the models’ actual and potential skill are sensitive to the number of ensemble members and type of ensemble generation. Moreover, the GloSea5 model actual skill is higher than the NEPS-G model over Indian homogeneous regions. To use the GloSea5 NWP forecast model ensemble members for more quantitative applications in downstream hazard and/or impact-based modelling and applications the between-ensemble-member bias introduced by the lagging needs to be addressed.

The UK Inshore Waters Forecast predicts wind speeds, sea states, weather conditions and visibilities for marine areas within 12 nautical miles of the UK coast. In addition to the now-common web-based outlets of most public forecast products, this very high profile forecast product is also broadcast by the BBC on national radio and television. It is the enviable task of Operational Meteorologists, based at UK Met Office sites in Exeter and Aberdeen, to issue these forecasts every six hours for the vitally important purpose of protecting lives in the coastal waters surrounding the UK. Currently, the production process involves a marine forecaster comprehensively inspecting deterministic model fields, prior to manual text generation. However, direct utilisation of an ensemble model-based product has the potential to make this task considerably more efficient and possibly make the forecast more accurate.Raw output from the Met Office Global and Regional Ensemble Prediction System (MOGREPS) is used routinely throughout the Met Office to assist forecasters. Furthermore, a recent project to develop and improve the techniques used to statistically post-process this data (IMPROVER) is now employed to further reduce identified errors within MOGREPS data.This session describes the latest work to exploit both raw MOGREPS and post-processed data for the generation of the wind component to the Inshore Waters Forecast. This component is verified against post-processed nowcast analysis fields to determine its accuracy and the results are compared against the equivalent performance currently achieved by Operational Maritime Meteorologists. The outcome of this assessment will help to determine whether either of these data-sources are suitable as a guide for the production of this high-profile forecast product.

Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic cell transplantation (HCT) occurring in approximately 60-70% of CMV-seropositive HCT recipients. CMV reactivation leads to adverse outcomes including end-organ damage, graft-versus-host disease, and graft failure.Ganciclovir was administered pretransplant at 5 mg/kg twice daily intravenously from the start of conditioning to Day T-2 to CMV-seropositive patients receiving their first allogeneic HCT. CMV DNA was monitored weekly until at least Day 100 posttransplant.A total of 109 consecutive patients were treated, median age 57 (range 20-73) years. Of these, 36 (33%) patients had a CMV reactivation within the first 105 days posttransplant with a median time of reactivation of 52.5 (range 36-104) days posttransplant. The cumulative incidence of CMV reactivation at Day 105 posttransplant was 33.1% (95% confidence interval: 24.4-42.0). One patient developed CMV disease.The use of pretransplant ganciclovir was associated with low incidence of CMV reactivation and disease. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation may be a useful strategy to reduce CMV reactivation. Future prospective trials are needed to compare strategies for CMV prophylaxis.

There are important efforts being made to revitalise Aboriginal languages in Australia, which are both pedagogically and culturally appropriate. This research seeks to expand the current knowledge of the effectiveness of gesturing as a teaching strategy for young children learning the Gathang language. An experimental method was used to investigate the effectiveness of gesture by employing a context in which other variables (e.g., other teaching pedagogies) could be held constant. Participants, age range 4–5.2 years, were taught Gathang nouns with gesture and without gesture, alongside verbal and pictorial instruction. After the teaching sessions, each child was assessed for their receptive and expressive knowledge of the Gathang nouns, at two time points, two days after instruction (post-test 1) and one week after (post-test 2). At post-test 2, children had stronger receptive knowledge for words they had learned with gesture than without. These findings contribute to a growing body of research attesting to the effectiveness of gesture for improving knowledge acquisition amongst learners. In the context of Aboriginal language revitalisation, gesture also aligns with traditional teaching practices and offers a relatively low-cost strategy for helping teachers assist their students in acquiring Aboriginal languages.

Introduction Sudden cardiac death is the most common cause of mortality in childhood onset hypertrophic cardiomyopathy. Identifying individuals at highest risk is therefore an essential part of clinical care but remains challenging. The 12 lead electrocardiogram (ECG) has been proposed as a useful tool for risk stratification and an ECG risk score has been proposed. However, this has not been independently validated and the ECG phenotype of childhood HCM has not been previously described. The aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods Participants with an available baseline resting 12-lead ECG were identified from a large, international, multi-centre, retrospective cohort of patients aged less than 16 years fulfilling the diagnostic criteria for HCM (n=1029). Resting baseline ECG was evaluated and ECG variables were extracted. In addition, the ECG risk score based on 8 parameters (deviation in QRS axis, pathological T-wave inversion in limb or precordial leads, ST-segment depression, dominant S-wave in V4, limb-lead amplitude sum, 12-lead amplitude duration product and QTc) was calculated as previously described. The primary study endpoint was a composite outcome of major cardiac events (MACE) defined as SCD, resuscitated cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia (VT) with haemodynamic compromise. The discriminatory performance of using an ECG risk score >5 to identify patients at increased risk of MACE at 5 years was determined using Harrell’s C-index. Results Of 356 patients with childhood HCM (68.9% male, mean age at presentation 10.1 ± 4.5 years), 347 (97.5%) had baseline ECG abnormalities such as: repolarization abnormalities (n=277, 77.8%), left ventricular hypertrophy (n=240. 67.6%), abnormal QRS axis (n=126, 35.4%) or QT prolongation (n=131, 36.8%). Over a median follow up of 3.9 years (IQR 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year MACE on univariable or multivariable Cox regression analysis. Of the 164 participants with an ECG score >5, 153 (93.3%) did not have a MACE within 5 years. Harrell’s C-index (the probability of correctly distinguishing between high and low risk patients using an ECG risk score threshold of >5) was 0.60 (95% CI 0.484-0.715) at 5 years. The corresponding positive and negative predictive values were 6.7% (95% CI 4.7 – 9.4%) and 96.9% (95% CI 94.2 – 98.4%). Conclusions In a large, international, multi-centre cohort of children with HCM, ECG abnormalities are common. No ECG characteristic, either in isolation or combined in the ECG risk score, was associated with 5-year MACE risk. This suggests that the role of the baseline ECG phenotype in improving risk stratification in childhood HCM is limited. Conflict of Interest None

ObjectiveHypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich’s ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM.Design and settingRetrospective, longitudinal cohort study of children with FA-HCM from the UK.Patients78 children (InterventionAnonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up.Main outcome measuresThe primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation.ResultsThe mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4–7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8).ConclusionsThis is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.

Background and Aims At least 80% of children with steroid sensitive nephrotic syndrome (SSNS) have relapses and many are triggered by upper respiratory tract infections (URTIs). Previous small studies (4 studies, 232 patients in total), mostly in children already taking maintenance corticosteroid in countries where URTI epidemiology is different to Europe, showed that giving daily low-dose prednisolone for 5-7 days during an URTI reduces the risk of relapse. The objective of the PREDNOS 2 trial was to determine if these findings were replicated in a large UK population of children with relapsing SSNS on different background medication or none. Method A randomised, double-blind, placebo-controlled trial, including a model-based economic evaluation was carried out in 122 UK paediatric departments. Between February 2013 and January 2019, 365 children with relapsing SSNS (mean age: 7.6 ± 3.5 y) were recruited from 91 sites and randomised (1:1) according to a minimisation algorithm based on background treatment (no background treatment; low-dose prednisolone only; low-dose prednisolone and other immunosuppression; other immunosuppression only). At the start of an URTI, children received 6 days of prednisolone 15 mg/m2 or matching preparation of placebo. Those already taking alternate day prednisolone rounded their daily dose using trial medication to the equivalent of 15 mg/m2 or their alternate-day dose, whichever was the greater. The primary outcome was the incidence of first URTI-related relapse (URR) following any URTI over 12 months. Secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention to treat. The economic evaluation used trial data and a decision-analytic model to estimate Quality-Adjusted-Life-Years (QALYs) and costs at 1-year, which were then extrapolated over 16 years. Results 80 children completed 12 m follow-up without an URTI. Consent was withdrawn for 32 children, 14 prior to an URTI, leaving a modified intention to treat analysis population of 271 children (134 and 137 in prednisolone and placebo arms respectively). There were 384 URTIs and 82 URRs in the prednisolone arm, and 407 URTIs and 82 URRs in the placebo arm. The number of patients experiencing a URR was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms respectively (adjusted risk difference: -0.024, 95% CI: -0.14 to 0.095; P=0.7). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. A post-hoc subgroup analysis assessing primary outcome in 58 children of South Asian ethnicity (RR 0.66, 95% CI: 0.396 to 1.105) versus 213 of other ethnicity (RR 1.11, 95% CI: 0.806 to 1.535) showed possible efficacy of intervention in those of South Asian ethnicity (test for interaction P=0.09). Giving daily prednisolone at the time of an URTI was found to increase QALYs and decrease overall costs, when compared to standard care, a finding that was robust to sensitivity analysis. Conclusion In a large and methodologically-robust study, PREDNOS 2 has shown that giving 6 days of daily low-dose prednisolone at the time of an URTI does not reduce the risk of relapse of nephrotic syndrome in UK children, but could offer a cost-effective use of health care resources. Further work is needed to investigate inter-ethnic differences in treatment response, and the pathogenesis of individual viral infections and their effect on nephrotic syndrome.

Overlapping clinical features promoted the discussion of whether Kawasaki disease (KD) and PIMS-TS share pathophysiological features and disease outcomes. Medical records from English patients with KD (2015-02/20, N = 27) and PIMS-TS (02/2020-21, N = 34) were accessed to extract information. Children with PIMS-TS were older and more frequently of minority ethnicity background. They patients more commonly exhibited cytopenias and hyperferritinemia, which associated with diffuse cardiac involvement and functional impairment. In some PIMS-TS cases, cardiac pathology developed late, but outcomes were more favorable. In both, KD and PIMS-TS, baseline coronary diameter was a predictor of outcomes. PIMS-TS treatment more frequently included respiratory and cardiovascular support, and corticosteroids with IVIG. Cardiac involvement in PIMS-TS may be the result of a cytokine storm. Though more severe and diffuse when compared to KD, cardiac involvement of PIMS-TS has a more favorable prognosis, which may, after recovery, mitigate the need for long-term follow up.

Summary Background In malaria-endemic areas, residents of modern houses have less malaria than those living in traditional houses. We aimed to assess whether children in The Gambia received an incremental benefit from improved housing, where current best practice of insecticide-treated nets, indoor residual spraying, seasonal malaria chemoprevention in children younger than 5 years, and prompt treatment against clinical malaria was in place. Methods In this randomised controlled study, 800 households with traditional thatched-roofed houses were randomly selected from 91 villages in the Upper River Region of The Gambia. Within each village, equal numbers of houses were randomly allocated to the control and intervention groups using a sampling frame. Houses in the intervention group were modified with metal roofs and screened doors and windows, whereas houses in the control group received no modifications. In each group, clinical malaria in children aged 6 months to 13 years was monitored by active case detection over 2 years (2016–17). We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria in study children with more than 50% of observations each year and household vector density. The trial is registered at ISRCTN02622179. Findings In June, 2016, 785 houses had one child each recruited into the study (398 in unmodified houses and 402 in modified houses). 26 children in unmodified houses and 28 children in modified houses did not have at least 50% of visits in a year and so were excluded from analysis. 38 children in unmodified houses were recruited after study commencement, as were 21 children in modified houses, meaning 410 children in unmodified houses and 395 in modified houses were included in the parasitological analyses. At the end of the study, 659 (94%) of 702 children were reported to have slept under an insecticide-treated net; 662 (88%) of 755 children lived in houses that received indoor residual spraying; and 151 (90%) of 168 children younger than 5 years had seasonal malaria chemoprevention. Incidence of clinical malaria was 0·12 episodes per child-year in children in the unmodified houses and 0·20 episodes per child-year in the modified houses (unadjusted incidence rate ratio [RR] 1·68 [95% CI 1·11–2·55], p=0·014). Household vector density was 3·30 Anopheles gambiae per house per night in the unmodified houses compared with 3·60 in modified houses (unadjusted RR 1·28 [0·87–1·89], p=0·21). Interpretation Improved housing did not provide protection against clinical malaria in this area of low seasonal transmission with high coverage of insecticide-treated nets, indoor residual spraying, and seasonal malaria chemoprevention. Funding Global Health Trials funded by Medical Research Council, UK Department for International Development, and Wellcome Trust.

The bacterial pathogen responsible for causing Lyme disease, Borrelia burgdorferi, is an atypical Gram-negative spirochete that is transmitted to humans via the bite of an infected Ixodes tick. In diderms, peptidoglycan (PG) is sandwiched between the inner and outer membrane of the cell envelope. In many other Gram-negative bacteria, PG is bound by protein(s), which provide both structural integrity and continuity between envelope layers. Here, we present evidence of a peptidoglycan-associated protein (PAP) in B. burgdorferi. Using an unbiased proteomics approach, we identified Neutrophil Attracting Protein A (NapA) as a PAP. Interestingly, NapA is a Dps homologue, which typically functions to bind and protect cellular DNA from damage during times of stress. While B. burgdorferi NapA is known to be involved in the oxidative stress response, it lacks the critical residues necessary for DNA binding. Biochemical and cellular studies demonstrate that NapA is localized to the B. burgdorferi periplasm and is indeed a PAP. Cryo-electron microscopy indicates that mutant bacteria, unable to produce NapA, have structural abnormalities. Defects in cell-wall integrity impact growth rate and cause the napA mutant to be more susceptible to osmotic and PG-specific stresses. NapA-linked PG is secreted in outer membrane vesicles and augments IL-17 production, relative to PG alone. Using microfluidics, we demonstrate that NapA acts as a molecular beacon—exacerbating the pathogenic properties of B. burgdorferi PG. These studies further our understanding of the B. burgdorferi cell envelope, provide critical information that underlies its pathogenesis, and highlight how a highly conserved bacterial protein can evolve mechanistically, while maintaining biological function., Author summary Diderms typically produce peptidoglycan-associated proteins (PAPs) to enhance structural integrity and continuity within the cell envelope. We have identified a PAP in B. burgdorferi with structural and sequence homology to the near ubiquitous bacterial protein Dps (DNA binding protein from starved bacteria). The B. burgdorferi Dps paralogue is incapable of binding DNA. Instead, it bolsters the protective properties of the PG layer, while playing an important role in host immune modulation. Collectively, our findings highlight the plasticity of bacterial proteins in that they may change how they perform a task despite maintaining the same basic biological function.

The concepts of purity and contamination preoccupied early modern Europeans fundamentally, structuring virtually every aspect of their lives, not least how they created and experienced works of art and the built environment. In an era that saw a great number of objects and people in motion, the meteoric rise of new artistic and building technologies, and religious upheaval exert new pressures on art and its institutions, anxieties about the pure and the contaminated – distinctions between the clean and unclean, sameness and difference, self and other, organization and its absence – took on heightened importance. In this series of geographically and methodologically wide-ranging essays, thirteen leading historians of art and architecture grapple with the complex ways that early modern actors negotiated these concerns, covering topics as diverse as Michelangelo’s unfinished sculptures, Venetian plague hospitals, Spanish-Muslim tapestries, and emergency currency. The resulting volume offers surprising new insights into the period and into the modern disciplinary routines of art and architectural history.

Aims The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods and results Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7% Conclusion In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

The highly controlled migration of neutrophils toward the site of an infection can be altered when they are trained with lipopolysaccharides (LPS), with high dose LPS enhancing neutrophil migratory pattern toward the bacterial derived source signal and super-low dose LPS inducing either migration toward an intermediary signal or dysregulation and oscillatory movement. Empirical studies that use microfluidic chemotaxis-chip devices with two opposing chemoattractants showed differential neutrophil migration after challenge with different LPS doses. The epigenetic alterations responsible for changes in neutrophil migratory behavior are unknown. We developed two mathematical models that evaluate the mechanistic interactions responsible for neutrophil migratory decision-making when exposed to competing chemoattractants and challenged with LPS. The first model, which considers the interactions between the receptor densities of two competing chemoattractants, their kinases, and LPS, displayed bistability between high and low ratios of primary to intermediary chemoattractant receptor densities. In particular, at equilibrium, we observe equal receptor densities for low LPS (< 15ng/mL); and dominance of receptors for the primary chemoattractant for high LPS (> 15ng/mL). The second model, which included additional interactions with an extracellular signal-regulated kinase in both phosphorylated and non-phosphorylated forms, has an additional dynamic outcome, oscillatory dynamics for both receptors, as seen in the data. In particular, it found equal receptor densities in the absence of oscillation for super-low and high LPS challenge (< 0.4 and 1.1 376 ng/mL). Predicting the mechanisms and the type of external LPS challenge responsible for neutrophils migration toward pro-inflammatory chemoattractants, migration toward pro-tolerant chemoattractants, or oscillatory movement is necessary knowledge in designing interventions against immune diseases, such as sepsis., Frontiers in Genetics, 12, ISSN:1664-8021