Search

Background: Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by N-terminal domain (NTD)-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance of these antibodies in vivo is less clear. Methods: We characterized 1,213 SARS-CoV-2 spike (S)-binding mAbs derived from COVID-19 convalescent patients for binding specificity to the SARS-CoV-2 S protein, VH germ-line usage, and affinity maturation. Infection enhancement in a vesicular stomatitis virus (VSV)-SARS-CoV-2 S pseudovirus (PV) assay was characterized in respiratory and intestinal epithelial cell lines, and against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire was used to determine functional attributes of secreted NTD-binding mAbs. Results: We identified 72/1213 (5.9%) mAbs that enhanced SARS-CoV-2 infection in a PV assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least 5 months post-infection. Infection enhancement by NTD-binding mAbs was not observed in intestinal and respiratory epithelial cell lines and was diminished or lost against SARS-CoV-2 VOC. Proteomic deconvolution of the serum antibody repertoire from 2 of the convalescent patients identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum. Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins. Conclusions: Functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display functional attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.

Uncontrolled angiogenesis is a common denominator underlying many deadly and debilitating diseases such as myocardial infarction, chronic wounds, cancer, and age-related macular degeneration. As the current range of FDA-approved angiogenesis-based medicines are far from meeting clinical demands, the vast reserve of natural products from traditional Chinese medicine (TCM) offers an alternative source for developing pro-angiogenic or anti-angiogenic modulators. Here, we investigated 100 traditional Chinese medicine-derived individual metabolites which had reported gene expression in MCF7 cell lines in the Gene Expression Omnibus (GSE85871). We extracted literature angiogenic activities for 51 individual metabolites, and subsequently analysed their predicted targets and differentially expressed genes to understand their mechanisms of action. The angiogenesis phenotype was used to generate decision trees for rationalising the poly-pharmacology of known angiogenesis modulators such as ferulic acid and curculigoside and validated by an in vitro endothelial tube formation assay and a zebrafish model of angiogenesis. Moreover, using an in silico model we prospectively examined the angiogenesis-modulating activities of the remaining 49 individual metabolites. In vitro, tetrahydropalmatine and 1 beta-hydroxyalantolactone stimulated, while cinobufotalin and isoalantolactone inhibited endothelial tube formation. In vivo, ginsenosides Rb3 and Rc, 1 beta-hydroxyalantolactone and surprisingly cinobufotalin, restored angiogenesis against PTK787‐induced impairment in zebrafish. In the absence of PTK787, deoxycholic acid and ursodeoxycholic acid did not affect angiogenesis. Despite some limitations, these results suggest further refinements of in silico prediction combined with biological assessment will be a valuable platform for accelerating the research and development of natural products from traditional Chinese medicine and understanding their mechanisms of action, and also for other traditional medicines for the prevention and treatment of angiogenic diseases.

Abstract Background Haiti has the highest rate of neonatal mortality in the Latin America and Caribbean region. While the rate of facility births in Haiti has doubled over the past two decades, there have been no comparable reductions in maternal or neonatal mortality. Little data is available on the clinical characteristics of complications and morbidities among newborns requiring hospitalization after birth and their contribution to neonatal mortality. There is a need to better understand the status of newborn clinical care capacity in Haiti to prioritize training and resources. Methods We performed a retrospective observational cohort study of neonates admitted to a large public referral hospital in southern Haiti in the first 2 years of operation of a new neonatal unit that we established. All neonate cases hospitalized in the unit in these 2 years were reviewed and analyzed to identify their clinical characteristics and outcomes. Multivariable logistic regression was used to identify independent risk factors of hospital mortality. We present the outcomes for 1399 neonates admitted to the unit during August 2017 and August 2019. Results The leading cause of death was prematurity, followed by hypoxia and infection. Inborn neonates had better rates of hospital survival than those born elsewhere; they were also more likely to be born via cesarean section and to be admitted immediately following birth. There were no differences between the proportion of premature or low-birth-weight babies born at the hospital or elsewhere. Mortality in the second year of the unit’s operation was 12%, almost half that of the first year (21%). Multivariable regression analysis showed that mortality was consistently higher among premature and very low birthweight babies. Conclusions With modest investments, we were able to halve the mortality on a neonatal unit in Haiti. Resources are needed to address prematurity as an important outcome since hospital mortality was significant in this group. To this end, investment in uninterrupted supplies of oxygen and antibiotics, as well as ensuring adequate newborn resuscitation, infection control, laboratory testing, and timely morbidity and mortality reviews would go a long way toward lowering hospital mortality in Haiti.

Abstract Background Drug-induced liver injury (DILI) is a major safety concern characterized by a complex and diverse pathogenesis. In order to identify DILI early in drug development, a better understanding of the injury and models with better predictivity are urgently needed. One approach in this regard are in silico models which aim at predicting the risk of DILI based on the compound structure. However, these models do not yet show sufficient predictive performance or interpretability to be useful for decision making by themselves, the former partially stemming from the underlying problem of labeling the in vivo DILI risk of compounds in a meaningful way for generating machine learning models. Results As part of the Critical Assessment of Massive Data Analysis (CAMDA) “CMap Drug Safety Challenge” 2019 ( http://camda2019.bioinf.jku.at ), chemical structure-based models were generated using the binarized DILIrank annotations. Support Vector Machine (SVM) and Random Forest (RF) classifiers showed comparable performance to previously published models with a mean balanced accuracy over models generated using 5-fold LOCO-CV inside a 10-fold training scheme of 0.759 ± 0.027 when predicting an external test set. In the models which used predicted protein targets as compound descriptors, we identified the most information-rich proteins which agreed with the mechanisms of action and toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs), one of the most important drug classes causing DILI, stress response via TP53 and biotransformation. In addition, we identified multiple proteins involved in xenobiotic metabolism which could be novel DILI-related off-targets, such as CLK1 and DYRK2. Moreover, we derived potential structural alerts for DILI with high precision, including furan and hydrazine derivatives; however, all derived alerts were present in approved drugs and were over specific indicating the need to consider quantitative variables such as dose. Conclusion Using chemical structure-based descriptors such as structural fingerprints and predicted protein targets, DILI prediction models were built with a predictive performance comparable to previous literature. In addition, we derived insights on proteins and pathways statistically (and potentially causally) linked to DILI from these models and inferred new structural alerts related to this adverse endpoint.

There is an urgent need to reduce global greenhouse gas emissions. One method of achieving this is through Carbon Capture and Storage (CCS). Geological structures that lie offshore under continental shelf seas offer huge CCS storage potential. An emerging marine industry is developing to exploit this potential and national marine monitoring agencies will soon need to consider the potential impacts of this emerging industry. This review of published literature is aimed at generalists responsible for the delivery of national marine monitoring, as well as those involved in the management of the marine environment. It briefly summarizes why the emerging offshore CCS industry is needed, how large it may be and what marine infrastructure may be involved. For the purposes of this paper, a hypothetical 20 Mtpa industry has been used to gauge the potential impact of a developing offshore CCS industry. The probability of CO2 leaks from such an industry is low. If they do occur, the spatial scale of impact will be small, and the potential environmental impacts will be low. Irrespective of how CO2 is transported or stored within shelf seas, leaked CO2 will enter the sea as a gas or as a solution dissolved in sediment pore water. CO2 as a gas will dissolve into seawater and/or directly vent to the atmosphere, depending on the initial conditions of the leak. The most probable source of leaks in a developed CCS industry is from pipelines (currently a 2-year event per 1000 km pipeline). The most probable source of leakage from geological storage is through abandoned wells (a 20- to 80-year event for a 20 Mtpa industry). The source of leaks from a CCS scheme with the potential to release the greatest mass of CO2 is through geological faults, as these may go undetected (if they occur) for long periods. The probability of leaks from geological storage, through faults or abandoned wells, is site dependent and minimized by the site selection process. The review concludes with recommended priorities for future marine science development.

ObjectivePhysical activity (PA) counselling has been shown to raise awareness of the importance of PA and to increase the rate of PA engagement among patients. While much attention has been paid to examining the knowledge, attitudes and practice of general practitioners in relation to PA counselling, there is less literature examining such issues in hospital-based doctors in Ireland and further afield. This study aimed to explore doctors’ PA counselling practices and to analyse how this related to their level of PA knowledge, training and attitudes.MethodsAn invitation to participate in an online survey was sent to 4692 members of the Royal College of Physicians of Ireland who were listed as having an address in Ireland. Descriptive and explorative analyses of the data were performed using IBM SPSS V.22.0.ResultsA total of 595 valid responses were included (response rate 12.7%; 42.7% male, 42.6±12.1 years). The majority reported enquiring about PA levels (88.0%) and providing PA counselling (86.4%) in at least some of their patients. Doctors who saw it as their role and those who felt more effective/confident in providing PA counselling were significantly more likely to do so. A perceived lack of patient interest in PA and patient preference for pharmaceutical intervention were significant barriers to undertaking PA counselling.ConclusionThis study demonstrates the need for further education and training in PA counselling in Ireland with a particular focus on improving the attitudes and self-efficacy of doctors in this area at both undergraduate and postgraduate levels.

cAMP/PKA signalling plays important roles in physiology, but there are a lack of tools to spatially distinguish cAMP. Here the authors present a FRET-based cAMP biosensor they call CUTie that can directly compare cAMP signals at multiple subcellular sites and detect nanoscale heterogeneity in cAMP in cardiac myocytes.

As our living environments, homes should be expected to house objects with which we are comfortable. This applies equally to the technology we introduce to our domestic environments: it should be blended or embedded within them, or at least intuitive and unobtrusive in the space. In this paper, we survey a number of the latest Organic User Interfaces (OUIs) and discuss how these novel designs can be adopted to help build future domestic smart environments. In this sense, interior spaces, surfaces (walls, floors, tables and ceilings), and interior objects such as furniture and decorative accessories can become computationally-driven interactive artefacts, potentially changing their physical appearances, i.e., shape, colour, pattern or texture. We believe that Human-Building Interaction (HBI) will soon evolve to develop and employ OUIs in domestic environments, dynamically supporting our personal preferences and enhancing our living experiences. We propose some of the potential benefits of ‘OUI Interiors’ such as employing familiar intuitive interactions, supporting psychological and physiological wellbeing of inhabitants and the opportunity of designing multifaceted aesthetic interiors. Moreover, we highlight some of the challenges to building interactive interior objects, furniture and accessories, such as supporting sustained user engagements over time and designing for daily use within domestic environments with all its social, ethical and behavioural implications.

BackgroundScalable weight loss maintenance (WLM) interventions for adults with obesity are lacking but vital for the health and economic benefits of weight loss to be fully realised. We examined the effectiveness and cost-effectiveness of a low-intensity technology-mediated behavioural intervention to support WLM in adults with obesity after clinically significant weight loss (≥5%) compared to standard lifestyle advice.Methods and findingsThe NULevel trial was an open-label randomised controlled superiority trial in 288 adults recruited April 2014 to May 2015 with weight loss of ≥5% within the previous 12 months, from a pre-weight loss BMI of ≥30 kg/m2. Participants were self-selected, and the majority self-certified previous weight loss. We used a web-based randomisation system to assign participants to either standard lifestyle advice via newsletter (control arm) or a technology-mediated low-intensity behavioural WLM programme (intervention arm). The intervention comprised a single face-to-face goal-setting meeting, self-monitoring, and remote feedback on weight, diet, and physical activity via links embedded in short message service (SMS). All participants were provided with wirelessly connected weighing scales, but only participants in the intervention arm were instructed to weigh themselves daily and told that they would receive feedback on their weight. After 12 months, we measured the primary outcome, weight (kilograms), as well as frequency of self-weighing, objective physical activity (via accelerometry), psychological variables, and cost-effectiveness. The study was powered to detect a between-group weight difference of ±2.5 kg at follow-up. Overall, 264 participants (92%) completed the trial. Mean weight gain from baseline to 12 months was 1.8 kg (95% CI 0.5-3.1) in the intervention group (n = 131) and 1.8 kg (95% CI 0.6-3.0) in the control group (n = 133). There was no evidence of an effect on weight at 12 months (difference in adjusted mean weight change from baseline: -0.07 [95% CI 1.7 to -1.9], p = 0.9). Intervention participants weighed themselves more frequently than control participants and were more physically active. Intervention participants reported greater satisfaction with weight outcomes, more planning for dietary and physical activity goals and for managing lapses, and greater confidence for healthy eating, weight loss, and WLM. Potential limitations, such as the use of connected weighing study in both trial arms, the absence of a measurement of energy intake, and the recruitment from one region of the United Kingdom, are discussed.ConclusionsThere was no difference in the WLM of participants who received the NULevel intervention compared to participants who received standard lifestyle advice via newsletter. The intervention affected some, but not all, process-related secondary outcomes of the trial.Trial registrationThis trial is registered with the ISRCTN registry (ISRCTN 14657176; registration date 20 March 2014).

Chronic illness models are normally used to explain and predict the experience of living with a long-term condition. The aim of this study was to present the findings of narrative interviews with stroke survivors and their family carers to understand their experiences of stroke. We interviewed five people with stroke and three family carers from the United Kingdom. We used thematic analysis to generate themes from their narrative accounts and then linked them to broader theoretical perspectives while influenced by the concept of reinterpretation of life. The narrative accounts of participants are mainly structured based on how their changed bodies poststroke changed their identities and roles and consequently their relationships with others. In this study, we underline the need for using methods like narrative to explain strategies that people use to make sense of their experiences of living with a long-term condition such as stroke.

In this paper, we present a two-part study. The first part was a cultural appreciation study. Through this study, we explored the specific approach of cross-cultural aesthetic appreciation and mapped out the potential insights for a prototype design. In the second part, we carried out a design-led study. We designed a tablet application and conducted focus group studies to explore the interactive technology that assists in the support of cross-cultural audiences’ aesthetic appreciation and engagement of traditional Chinese painting. Based on these findings, we went on to further explore an approach of interactive engagement which is specific to supporting cross-cultural appreciation, while also reflecting upon the interactive design suggestions for the development of aesthetic appreciation to offer various transferable insights to the Human–Computer Interaction (HCI) community.

An outbreak of cryptosporidiosis occurred in and around Clitheroe, Lancashire, in northwest England, during March 2000. Fifty-eight cases of diarrhea with Cryptosporidium identified in stool specimens were reported. Cryptosporidium oocysts were identified in samples from the water treatment works as well as domestic taps. Descriptive epidemiology suggested that drinking unboiled tap water in a single water zone was the common factor linking cases. Environmental investigation suggested that contamination with animal feces was the likely source of the outbreak. This outbreak was unusual in that hydrodynamic modeling was used to give a good estimate of the peak oocyst count at the time of the contamination incident. The oocysts’ persistence in the water distribution system after switching to another water source was also unusual. This persistence may have been due to oocysts being entrapped within biofilm. Despite the continued presence of oocysts, epidemiologic evidence suggested that no one became ill after the water source was changed.

We write this Editorial Overview having traveled together and separately through the articles in this Special Issue and offer it as a roadmap for your own exploration of the Issue. We are hopeful that you will use it to guide your reading, returning to it often, and that you will stop at each article to explore what it has to offer you. Enjoy the journey. Don't forget to collect souvenirs and remember to leave something of yourself. URN: urn:nbn:de:0114-fqs0802649

Introduction. The strategies that people use to browse Websites are difficult to analyse and understand: quantitative data can lack information about what a user actually intends to do, while qualitative data tends to be localised and is impractical to gather for large samples. Method. This paper describes a novel approach that combines data from direct observation, user surveys and server logs to analyse users' browsing behaviour. It is based on a longitudinal study of university students' use of a Website related to one of their courses. Analysis. The data were analysed by using Footstep graphs to categorise browsing behaviour into pre-defined strategies and comparing these with data from questionnaires and direct observation of the students' actual use of the site. Results. Initial results indicated that in certain cases the patterns from server logs matched the observed browsing strategies as described in the literature. In addition, by cross-referencing the quantitative and qualitative data, a number of insights were gained into potential problems. Conclusion. This study shows how combining quantitative and qualitative approaches can provide an insight into changes in user browsing behaviour over time. It also identifies some potential methodological problems in studies of browsing behaviour and indicates some directions for future research.

OBJECTIVES: To describe the effectiveness of a program designed to reduce the rate of mother-to-child transmission (MTCT) of HIV at the primary HIV testing and treatment center in Haiti between 1999 and 2004. METHODS: All pregnant, HIV-positive women who attended the major HIV testing and treatment clinic in Port-au-Prince, Haiti, between March 1999 and December 2004 were asked to participate in an MTCT prevention program. Of the 650 women who participated, 73.3% received zidovudine (AZT), 2.9% received nevirapine (NVP), and 10.1% received triple-drug therapy when it became available in 2003 and if clinical/laboratory indications were met. Approximately 13.8% received no antiretroviral medication. All participants received cotrimoxazole prophylaxis and infant formula for their children. Kaplan-Meier survival analysis and the log rank test were used to evaluate program impact on child survival. RESULTS: Complete data were available for 348 mother-infant pairs who completed the program to prevent MTCT of HIV. The rate of MTCT in the study was 9.2% (95% CI: 6.14-12.24), in contrast to the historical mother-to-child transmission rate of 27% in Haiti. HIV-positive infants were less likely to survive than HIV-negative infants at 18 months of follow-up (χ2 = 19.06, P < .001, log rank test). Infant survival improved with early pediatric diagnosis and antiretroviral treatment. CONCLUSIONS: The MTCT prevention program described proved to be feasible and effective in reducing vertical HIV transmission in Haiti. The authors emphasize the need to expand testing, extend services to rural areas, and implement early HIV diagnosis to reduce infant mortality.