How deep is AI's love? Understanding relational AI.

We suggest that as people move to construe robots as social agents, interact with them, and treat them as capable of social ties, they might develop (close) relationships with them. We then ask what kind of relationships can people form with bots, what functions can bots fulfill, and what are the societal and moral implications of such relationships.

Software engineering standards for epidemiological models.

There are many tangled normative and technical questions involved in evaluating the quality of software used in epidemiological simulations. In this paper we answer some of these questions and offer practical guidance to practitioners, funders, scientific journals, and consumers of epidemiological research. The heart of our paper is a case study of the Imperial College London (ICL) covid-19 simulator, set in the context of recent work in epistemology of simulation and philosophy of epidemiology.

Building the foundations for sustainable development: a case for global investment in the capabilities of adolescents.

Investment in the capabilities of the world's 1·2 billion adolescents is vital to the UN's Sustainable Development Agenda. We examined investments in countries of low income, lower-middle income, and upper-middle income covering the majority of these adolescents globally to derive estimates of investment returns given existing knowledge. The costs and effects of the interventions were estimated by adapting existing models and by extending methods to create new modelling tools. Benefits were valued in terms of increased gross domestic product and averted social costs. The initial analysis showed high returns for the modelled interventions, with substantial variation between countries and with returns generally higher in low-income countries than in countries of lower-middle and upper-middle income. For interventions targeting physical, mental, and sexual health (including a human papilloma virus programme), an investment of US$4·6 per capita each year from 2015 to 2030 had an unweighted mean benefit to cost ratio (BCR) of more than 10·0, whereas, for interventions targeting road traffic injuries, a BCR of 5·9 (95% CI 5·8-6·0) was achieved on investment of $0·6 per capita each year. Interventions to reduce child marriage ($3·8 per capita each year) had a mean BCR of 5·7 (95% CI 5·3-6·1), with the effect high in low-income countries. Investment to increase the extent and quality of secondary schooling is vital but will be more expensive than other interventions-investment of $22·6 per capita each year from 2015 to 2030 generated a mean BCR of 11·8 (95% CI 11·6-12·0). Investments in health and education will not only transform the lives of adolescents in resource-poor settings, but will also generate high economic and social returns. These returns were robust to substantial variation in assumptions. Although the knowledge base on the impacts of interventions is limited in many areas, and a major research effort is needed to build a more complete investment framework, these analyses suggest that comprehensive investments in adolescent health and wellbeing should be given high priority in national and international policy.

Impact of age on the vasodilatory function of human skeletal muscle feed arteries.

Although advancing age is often associated with attenuated skeletal muscle blood flow and skeletal muscle feed arteries (SMFAs) have been recognized to play a regulatory role in the vasculature, little is known about the impact of age on the vasodilatory capacity of human SMFAs. Therefore, endothelium-dependent and -independent vasodilation were assessed in SMFAs (diameter: 544 ± 63 µm) obtained from 24 (equally represented) young (33 ± 2 yr) and old (71 ± 2 yr) subjects in response to three stimuli: 1) flow-induced shear stress, 2) ACh, and 3) sodium nitropusside (SNP). Both assessments of endothelium-dependent vasodilation, flow (young subjects: 68 ± 1% and old subjects: 32 ± 7%) and ACh (young subjects: 92 ± 3% and old subjects: 73 ± 4%), were significantly blunted (P < 0.05) in SMFAs of old compared with young subjects, with no such age-related differences in endothelium-independent vasodilation (SNP). In response to an increase in flow-induced shear stress, vasodilation kinetics (time constant to reach 63% of the amplitude of the response: 55 ± 1 s in young subjects and 92 ± 7 s in old subjects) and endothelial nitric oxide synthase (eNOS) activation (phospho-eNOS(s1177)/total eNOS: 1.0 ± 0.1 in young subjects and 0.2 ± 0.1 in old subjects) were also significantly attenuated in old compared with young subjects (P < 0.05). Furthermore, the vessel superoxide concentration was greater in old subjects (old subjects: 3.9 ± 1.0 area under curve/mg and young subjects: 1.7 ± 0.1 area under the curve/mg, P < 0.05). These findings reveal that the endothelium-dependent vasodilatory capacity, including vasodilation kinetics but not smooth muscle function, of human SMFAs is blunted with age and may be due to free radicals. Given the potential regulatory role of SMFAs in skeletal muscle blood flow, these findings may explain, at least in part, the often observed attenuated perfusion of skeletal muscle with advancing age that may contribute to exercise intolerance in the elderly.

Catheter ablation of atrial fibrillation: anticipating and avoiding complications.

INTRODUCTION: Atrial fibrillation (AF) ablation is being performed more frequently and more widely at more centers. This stems from several factors including 1) demographic forces leading to an increased prevalence of the arrhythmia; 2) greater availability of ambulatory monitoring making diagnosis more frequent; 3) relative inefficacy of medications; and 4) improved safety and efficacy of the procedure. Ablation has become much more streamlined and reproducible than a decade ago, but life-threatening complications may still arise. AREAS COVERED: This review will focus on awareness, avoidance, and early recognition and management of complications of AF ablation. This literature review is challenged by differing approaches to ablation of AF both within a center and between centers, the rapid improvement of technology making the outcomes associated with a therapeutic strategy begun a few years prior relatively obsolete, as well as the heterogeneity of the population being studied. EXPERT OPINION: Newer technologies are on the horizon which will allow us to ablate AF with increasing efficacy, efficiency, and hopefully safety. Such new technology and changing usage mandate vigilance to avoid complications.

Activating P2Y1 receptors improves function in arteries with repressed autophagy.

AIM: The importance of endothelial cell (EC) autophagy to vascular homeostasis in the context of health and disease is evolving. Earlier, we reported that intact EC autophagy is requisite to maintain shear-stress-induced nitric oxide (NO) generation via glycolysis-dependent purinergic signalling to endothelial NO synthase (eNOS). Here, we illustrate the translational and functional significance of these findings. METHODS AND RESULTS: First, we assessed translational relevance using older male humans and mice that exhibit blunted EC autophagy and impaired arterial function vs. adult controls. Active hyperaemia evoked by rhythmic handgrip exercise-elevated radial artery shear-rate similarly from baseline in adult and older subjects for 60 min. Compared with baseline, indexes of autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs obtained from adult but not older volunteers. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older animals that completed 60-min treadmill-running. Furthermore, 20 dyne • cm2 laminar shear stress × 45-min increased autophagic flux, glycolysis, ATP production, and p-eNOSS1177 in primary arterial ECs obtained from adult but not older mice. Concerning functional relevance, we next questioned whether the inability to initiate EC autophagy, glycolysis, and p-eNOSS1177in vitro precipitates arterial dysfunction ex vivo. Compromised intraluminal flow-mediated vasodilation displayed by arteries from older vs. adult mice was recapitulated in vessels from adult mice by (i) NO synthase inhibition; (ii) acute autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) purinergic 2Y1-receptor (P2Y1-R) blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy. CONCLUSIONS: Arterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.

Gut Microbes Are Associated with the Vascular Beneficial Effects of Dietary Strawberry on Metabolic Syndrome-Induced Vascular Inflammation.

SCOPE: Metabolic syndrome (MetS) alters the gut microbial ecology and increases the risk of cardiovascular disease. This study investigates whether strawberry consumption reduces vascular complications in an animal model of MetS and identifies whether this effect is associated with changes in the composition of gut microbes. METHODS AND RESULTS: Seven-week-old male mice consume diets with 10% (C) or 60% kcal from fat (high-fat diet fed mice; HF) for 12 weeks and subgroups are fed a 2.35% freeze-dried strawberry supplemented diet (C+SB or HF+SB). This nutritional dose is equivalent to ≈160 g of strawberry. After 12 weeks treatment, vascular inflammation is enhanced in HF versus C mice as shown by an increased monocyte binding to vasculature, elevated serum chemokines, and increased mRNA expression of inflammatory molecules. However, strawberry supplementation suppresses vascular inflammation in HF+SB versus HF mice. Metabolic variables, blood pressure, and indices of vascular function were similar among the groups. Further, the abundance of opportunistic microbe is decreased in HF+SB. Importantly, circulating chemokines are positively associated with opportunistic microbes and negatively associated with the commensal microbes (Bifidobacterium and Facalibaculum). CONCLUSION: Dietary strawberry decreases the abundance of opportunistic microbe and this is associated with a decrease in vascular inflammation resulting from MetS.

Value judgments in a COVID-19 vaccination model: A case study in the need for public involvement in health-oriented modelling.

Scientific modelling is a value-laden process: the decisions involved can seldom be made using 'scientific' criteria alone, but rather draw on social and ethical values. In this paper, we draw on a body of philosophical literature to analyze a COVID-19 vaccination model, presenting a case study of social and ethical value judgments in health-oriented modelling. This case study urges us to make value judgments in health-oriented models explicit and interpretable by non-experts and to invite public involvement in making them.

Focally Appearing Activation Map of a Reentrant Tachycardia Using a New Coherent Mapping Tool.

Here, we discuss mapping of an atrioventricular reciprocating tachycardia (AVRT) using color-coding and a coherence module of the CARTO® mapping system (Biosense Webster, Diamond Bar, CA, USA). AVRT is a reentry tachycardia and, when the atrial exit site of the arrhythmia circuit was mapped in this case, it appeared to have a focal centrifugal activation pattern as depicted by coherent mapping.

Reduced Road Traffic Injuries for Young People: A Preliminary Investment Analysis.

PURPOSE: Deaths and serious injuries from road accidents remain a serious issue in developing countries, including for young people, for whom they are the largest cause of death. This article provides an assessment of interventions to reduce these deaths and injuries for adolescents in 75 developing countries. METHODS: We draw on new data on deaths and injuries by age, gender, and accident type for the 75 countries and on the road safety experience of developed and, more recently, developing countries. Critical tasks are to identify key interventions in road safety and estimate their impact and cost. We incorporate these impact and cost estimates in a modeling framework to calculate the reduction in deaths and serious injuries achieved out to 2030, relative to the base case. Finally, established methods are used to value the economic and social benefits arising from these reductions, and hence to calculate benefit-cost ratios. RESULTS: For the unchanged policy case, we estimate that there will be about 3 million deaths and 7.4 million serious injuries from road accidents for persons aged 10-24 years in the 75 countries to 2030. The preferred interventions avert one million of these deaths and 3 million serious injuries, at a cost of $6.5 billion per annum over 2016-2030, or $1.2 per capita across the total population of these countries. After valuing the benefits of the deaths and serious injuries averted, we find a benefit-cost ratio of 7.6 for 2016-2030, but of 9.9 if the interventions continue to 2050. CONCLUSIONS: Proven methods, suitably adjusted to local conditions, are available to reduce the tragic toll of road accidents in developing countries. These initiatives are likely to have strong economic and social returns, and should be given high priority.

Morphological differences between coastal bottlenose dolphin (Tursiops aduncus) populations identified using non-invasive stereo-laser photogrammetry.

Obtaining morphometric data on free-ranging marine megafauna is difficult, as traditional methods rely on post-mortem or live-capture techniques. We linked stereo-laser photogrammetry with long-term demographic data to compare length-at-age (LaA) growth curves of two well-studied populations of Indo-Pacific bottlenose dolphins (Tursiops aduncus) in south-western (SW) and Shark Bay (SB), mid-western Australia. First, we determined the relationship between total length (TL) and blowhole-to-dorsal fin (BH-DF) length from post-mortem subjects (R2 = 0.99, n = 12). We then predicted TL from laser-derived BH-DF measurements of 129 and 74 known-age individuals in SW and SB, respectively. Richards growth models best described our LaA data. While birth length (103-110 cm) was similar between study regions, TL estimates at 1, 3, 12, and 25 years differed significantly (p < 0.001). Asymptotic length of adult males (SW = 246 cm, SB = 201 cm) and females (SW = 244 cm, SB = 200 cm) also differed significantly. Morphotypic variations likely reflect regional adaptations to local water temperatures, with the temperate SW having cooler waters than sub-tropical SB. We demonstrate the effectiveness of a non-invasive technique to understand ecological, demographic and life-history characteristics of long-lived marine megafauna, which are critical parameters for informing conservation and management actions.

Expression of secreted frizzled related protein 1, a Wnt antagonist, in brain, kidney, and skeleton is dispensable for normal embryonic development.

Secreted frizzled related protein-1 (sFRP1), an antagonist of Wnt signaling, regulates cell proliferation, differentiation and apoptosis and negatively regulates bone formation. The spatial and temporal pattern of endogenous sFRP1 expression and loss-of-function were examined in the sFRP1-LacZ knock-in mouse (sFRP1-/-) during embryonic development and post-natal growth. beta-gal activity representing sFRP1 expression is robust in brain, skeleton, kidney, eye, spleen, abdomen, heart and somites in early embryos, but sFRP1 gene inactivation in these tissues did not compromise normal embryonic and post-natal development. Kidney histology revealed increased numbers of glomeruli in KO mice, observed after 5 years of breeding. In the skeleton, we show sFRP1 expression is found in relation to the mineralizing front of bone tissue during skeletal development from E15.5 to birth. Trabecular bone volume and bone mineral density in the sFRP1-/- mouse compared to WT was slightly increased during post-natal growth. Calvarial osteoblasts from newborn sFRP1-/- mice exhibited a 20% increase in cell proliferation and differentiation at the early stages of osteoblast maturation. sFRP1 expression was observed in osteoclasts, but this did not affect osteoclast number or activity. These findings have identified functions for sFRP1 in kidney and bone that are not redundant with other sFRPs. In summary, the absence of major organ abnormalities, the enhanced bone formation and a normal life span with no detection of spontaneous tumors suggests that targeting sFRP1 can be used as a therapeutic strategy for increasing bone mass in metabolic bone disorders or promoting fracture healing by modulating Wnt signaling.

Understanding and managing cancer of unknown primary.

As a nurse, it is important to understand, and to be able to meet, the informational needs of patients and their family caregivers. Comprehensive information can help to reduce the fear of a challenging diagnosis. In the case of cancer of unknown primary (CUP) it may be helpful to understand some of what is unknown as well as what is known of this phenomenon, which represents some 5% of cancer diagnoses (Pentheroudakis et al, 2007b). Drawing on the literature, this article focuses on definitions, characterization, categorization and treatment of CUP.

Impact of an education programme for staff working with children undergoing painful procedures.

AIM: Needle phobia is very common in children, particularly in those with chronic illness who may have to endure many painful procedures. A programme developed to educate paediatric healthcare professionals working with children undergoing painful procedures was evaluated to identify: (1) whether the education programme led to an increase in participating clinicians' knowledge and confidence; and (2) the effectiveness of the education programme in changing practice for patient care. METHOD: Five senior house officers undertook the one-hour training provided by the hospital play specialist. Questionnaires were completed by the clinicians at the beginning and end of the programme. Nurses reported on the clinicians' adherence to best practice. Twenty-one children who had undergone painful procedures were interviewed with their parents to assess their levels of pain, distress, satisfaction and coping style. RESULTS: Participants had increased their knowledge of how to work with children undergoing painful procedures. The main changes in knowledge reported by the clinicians were involving the nurse and the play specialist, preparing the equipment out of sight of the child and using distraction techniques. Parents and children reported low levels of distress during painful procedures, high levels of satisfaction with the procedure and listed a number of coping strategies that helped the child, and the parent, to cope during the procedure. Staff reports indicated that the protocol for painful procedures and that techniques such as distraction were being used in the majority of cases to help the child to cope. CONCLUSION: There are useful pain control techniques that can be taught relatively quickly by nursing staff to paediatric healthcare professionals that do make a substantial difference to the care of children.

Implications of survey effort on estimating demographic parameters of a long-lived marine top predator.

Effective management of wildlife populations rely on knowledge of their abundance, survival, and reproductive rates. Maintaining long-term studies capable of estimating demographic parameters for long-lived, slow-reproducing species is challenging. Insights into the effects of research intensity on the statistical power to estimate demographic parameters are limited. Here, we investigate implications of survey effort on estimating abundance, home range sizes, and reproductive output of Indo-Pacific bottlenose dolphins (Tursiops aduncus), using a 3-year subsample of a long-term, capture-recapture study off Bunbury, Western Australia. Photo-identification on individual dolphins was collected following Pollock's Robust Design, where seasons were defined as "primary periods", each consisting of multiple "secondary periods." The full dataset consisted of 12 primary periods and 72 secondary periods, resulting in the study area being surveyed 24 times/year. We simulated reduced survey effort by randomly removing one, two, or three secondary periods per primary period. Capture-recapture models were used to assess the effect of survey intensity on the power to detect trends in population abundance, while individual dolphin sighting histories were used to assess the ability to conduct home range analyses. We used sighting records of adult females and their calving histories to assess survey effort on quantifying reproductive output. A 50% reduction in survey effort resulted in (a) up to a 36% decline in population abundance at the time of detection; (b) a reduced ability to estimate home range sizes, by increasing the time for individuals to be sighted on ≥30 occasions (an often-used metric for home range analyses) from 7.74 to 14.32 years; and (c) 33%, 24%, and 33% of annual calving events across three years going undocumented, respectively. Results clearly illustrate the importance of survey effort on the ability to assess demographic parameters with clear implications for population viability analyses, population forecasting, and conservation efforts to manage human-wildlife interactions.

Differences in experiences of care between patients diagnosed with metastatic cancer of known and unknown primaries: mixed-method findings from the 2013 cancer patient experience survey in England.

OBJECTIVES: To explore differences in experiences of care reported in the Cancer Patient Experience Survey (CPES) between patients with cancer of unknown primary (CUP) and those with metastatic disease of known primary (non-CUP); to determine insights pertaining to the experiences of care for CUP respondents from free-text comments. DESIGN: Two separate, but related, studies, involving secondary analysis of existing data. Using frequency matching of CUP and non-CUP patients, statistical comparisons of responses to CPES questions were conducted. Free-text comments from CUP respondents were analysed thematically. SETTING AND PARTICIPANTS: The CPES questionnaire comprises 63 closed questions measuring 8 areas that relate to experience of care and 3 free-text questions. Questionnaires were mailed to all adult patients (aged ≥16 years) in England with cancer admitted to hospital between 1 September 2013 and 30 November 2013. RESULTS: Matched analysis of closed response items from 2992 patients found significant differences between CUP (n=1496) and non-CUP patients (n=1496): CUP patients were more likely to want more written information about their type of cancer and tests received, to receive their diagnosis from a general practitioner (GP) and have seen allied health professionals, but less likely to have understood explanations of their condition or had surgery. Freetext responses (n=3055) were coded into 17 categories and provided deeper insight regarding patient information and interactions with GPs. CPES data may include a preponderance of patients with favourable CUP subtypes and patients initially identified as CUP but whose primary was subsequently identified. CONCLUSIONS: These are the first large-scale studies to explore the experiences of care of CUP patients. The significant differences identified between the experiences of CUP and non-CUP patients suggest CUP patients require more psychosocial support and specific interventions to manage diagnostic uncertainty and the multiple investigations many CUP patients face. Substantial limitations were identified with the CPES data, emphasising the need for prospective studies.