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The ability to model morphological changes on complex, multi-landform coasts over decadal to centennial timescales is essential for sustainable coastal management worldwide. One approach involves coupling of landform-specific simulation models (e.g. cliffs, beaches, dunes and estuaries) that have been independently developed. An alternative, novel approach explored in this paper is to capture the essential characteristics of the landform-specific models using a common spatial representation within an appropriate software framework. This avoid the problems that result from the model-coupling approach due to between-model differences in the conceptualizations of geometries, volumes and locations of sediment. In the proposed framework, the Coastal Modelling Environment (CoastalME), change in coastal morphology is represented by means of dynamically linked raster and geometrical objects. A grid of raster cells provides the data structure for representing quasi-3-D spatial heterogeneity and sediment conservation. Other geometrical objects (lines, areas and volumes) that are consistent with, and derived from, the raster structure represent a library of coastal elements (e.g. shoreline, beach profiles and estuary volumes) as required by different landform-specific models. As a proof-of-concept, we illustrate the capabilities of an initial version of CoastalME by integrating a cliff–beach model and two wave propagation approaches. We verify that CoastalME can reproduce behaviours of the component landform-specific models. Additionally, the integration of these component models within the CoastalME framework reveals behaviours that emerge from the interaction of landforms, which have not previously been captured, such as the influence of the regional bathymetry on the local alongshore sediment-transport gradient and the effect on coastal change on an undefended coastal segment and on sediment bypassing of coastal structures.

Abstract Bacterial communities are ubiquitous, found in natural ecosystems, such as soil, and within living organisms, like the human microbiome. The dynamics of these communities in diverse environments depend on factors such as spatial features of the microbial niche, biochemical kinetics, and interactions among bacteria. Moreover, in many systems, bacterial communities are influenced by multiple physical mechanisms, such as mass transport and detachment forces. One example is gut mucosal communities, where dense, closely packed communities develop under the concurrent influence of nutrient transport from the lumen and fluid-mediated detachment of bacteria. In this study, we model a mucosal niche through a coupled agent-based and finite-volume modeling approach. This methodology enables us to model bacterial interactions affected by nutrient release from various sources while adjusting individual bacterial kinetics. We explored how the dispersion and abundance of bacteria are influenced by biochemical kinetics in different types of metabolic interactions, with a particular focus on the trade-off between growth rate and yield. Our findings demonstrate that in competitive scenarios, higher growth rates result in a larger share of the niche space. In contrast, growth yield plays a critical role in neutralism, commensalism, and mutualism interactions. When bacteria are introduced sequentially, they cause distinct spatiotemporal effects, such as deeper niche colonization in commensalism and mutualism scenarios driven by species intermixing effects, which are enhanced by high growth yields. Moreover, sub-ecosystem interactions dictate the dynamics of three-species communities, sometimes yielding unexpected outcomes. Competitive, fast-growing bacteria demonstrate robust colonization abilities, yet they face challenges in displacing established mutualistic systems. Bacteria that develop a cooperative relationship with existing species typically obtain niche residence, regardless of their growth rates, although higher growth yields significantly enhance their abundance. Our results underscore the importance of bacterial niche dynamics in shaping community properties and succession, highlighting a new approach to manipulating microbial systems.

Background: Relational continuity of care (patients seeing the same GP) is associated with better outcomes for patients, but it has been declining in general practice in the UK. Aim: To understand what interventions have been tried to improve relational continuity of care in general practice in the UK. Design & setting: Scoping review of articles on UK General Practice and written in English. Method: An electronic search of MEDLINE, Embase, and Scopus from 2002 to the present day was undertaken. Sources of grey literature were also searched. Studies that detailed service-level methods of achieving relational continuity of care with a GP in the UK were eligible for inclusion. Interventions were described narratively in relation to the elements listed in the Template for Intervention Description and Replication (TIDieR). A logic model describing the rationale behind interventions was constructed. Results: Seventeen unique interventions were identified. The interventions used a wide variety of strategies to try to improve relational continuity. This included personal lists, amended booking processes, regular reviews, digital technology, facilitated follow-ups, altered appointment times, and use of acute hubs. Twelve of the interventions targeted specific patient groups for increased continuity while others focused on increasing continuity for all patients. Changes in continuity levels were measured inconsistently using several different methods. Conclusion: Several different strategies have been used in UK general practices in an attempt to improve relational continuity of care. While there is a similar underlying logic to these interventions, their scope, aims, and methods vary considerably. Furthermore, owing to a weak evidence base, comparing their efficacy remains challenging.

Abstract Genetic variation in Arctic species is often influenced by vicariance during the Pleistocene, as ice sheets fragmented the landscape and displaced populations to low‐ and high‐latitude refugia. The formation of secondary contact or suture zones during periods of ice sheet retraction has important consequences on genetic diversity by facilitating genetic connectivity between formerly isolated populations. Brant geese (Branta bernicla) are a maritime migratory waterfowl (Anseriformes) species that almost exclusively uses coastal habitats. Within North America, brant geese are characterized by two phenotypically distinct subspecies that utilize disjunct breeding and wintering areas in the northern Pacific and Atlantic. In the Western High Arctic of Canada, brant geese consist of individuals with an intermediate phenotype that are rarely observed nesting outside this region. We examined the genetic structure of brant geese populations from each subspecies and areas consisting of intermediate phenotypes using mitochondrial DNA (mtDNA) control region sequence data and microsatellite loci. We found a strong east–west partition in both marker types consistent with refugial populations. Within subspecies, structure was also observed at mtDNA while microsatellite data suggested the presence of only two distinct genetic clusters. The Western High Arctic (WHA) appears to be a secondary contact zone for both Atlantic and Pacific lineages as mtDNA and nuclear genotypes were assigned to both subspecies, and admixed individuals were observed in this region. The mtDNA sequence data outside WHA suggests no or very restricted intermixing between Atlantic and Pacific wintering populations which is consistent with published banding and telemetry data. Our study indicates that, although brant geese in the WHA are not a genetically distinct lineage, this region may act as a reservoir of genetic diversity and may be an area of high conservation value given the potential of low reproductive output in this species.

This study investigated the strategies students in general chemistry and analytical chemistry courses used before and after instruction to solve a volumetric analysis problem in which the molar ratio was not 1:1. Questions like this have historically been very challenging for high school and undergraduate students. Student writing on open-response problems was analyzed to determine the problem-solving approach and identify errors made during the calculation. The two most prevalent strategies on pretests and post-tests were calculating mole amounts and using the equation M[subscript 1]V[subscript 1] = M[subscript 2]V[subscript 2]. Performance was significantly lower for students using the M[subscript 1]V[subscript 1] = M[subscript 2]V[subscript 2] as they often assumed a 1:1 molar ratio. The M[subscript 1]V[subscript 1] = M[subscript 2]V[subscript 2] heuristic was very popular despite its exclusion from formal instructional resources such as the textbook or lecture, and teachers seeking to improve instruction in this area must account for students using an approach not introduced in the classroom.

Abstract We recently introduced an absolute and physical quantitative scale for chromatin immunoprecipitation followed by sequencing (ChIP-seq). The scale itself was determined directly from measurements routinely made on sequencing samples without additional reagents or spike-ins. We called this approach sans spike-in quantitative ChIP, or siQ-ChIP. Herein, we extend those results in several ways. First, we simplified the calculations defining the quantitative scale, reducing practitioner burden. Second, we reveal a normalization constraint implied by the quantitative scale and introduce a new scheme for generating ‘tracks’. The constraint requires that tracks are probability distributions so that quantified ChIP-seq is analogous to a mass distribution. Third, we introduce some whole-genome analyses that allow us, for example, to project the IP mass (immunoprecipitated mass) onto the genome to evaluate how much of any genomic interval was captured in the IP. We applied siQ-ChIP to p300/CBP inhibition and compare our results to those of others. We detail how the same data-level observations are misinterpreted in the literature when tracks are not understood as probability densities and are compared without correct quantitative scaling, and we offer new interpretations of p300/CBP inhibition outcomes.

The infant non-secretor histoblood group antigen phenotype is associated with reduced risk of symptomatic rotavirus diarrhea, one of the leading global causes of severe pediatric diarrheal disease and mortality. However, little is known regarding the role of secretor status in asymptomatic rotavirus infections. Therefore, we performed a nested case–control study within a birth cohort study previously conducted in Dhaka, Bangladesh, to determine the association between infant secretor phenotype and the odds of asymptomatic rotavirus infection, in addition to the risk of rotavirus diarrhea, in unvaccinated infants. In the parent cohort, infants were enrolled in the first week of life and followed through the first two years of life with multiple clinic visits and active surveillance for diarrheal illness. Secretor phenotyping was performed on saliva. Eleven surveillance stools collected over the first year of life were tested for rotavirus by real-time RT-PCR, followed by conventional PCR and amplicon sequencing to identify the infecting P-type of positive specimens. Similar to findings for symptomatic diarrhea, infant non-secretors experienced significantly fewer primary episodes of asymptomatic rotavirus infection through the first year of life in a likely rotavirus P-genotype-dependent manner. These data suggest that non-secretors experienced reduced risk from rotavirus due to decreased susceptibility to infection rather than reduced infection severity.

Despite significant progress in recent decades toward ameliorating the excess burden of diarrheal disease globally, childhood diarrhea remains a leading cause of morbidity and mortality in low-and-middle-income countries (LMICs). Recent large-scale studies of diarrhea etiology in these populations have revealed widespread co-infection with multiple enteric pathogens, in both acute and asymptomatic stool specimens. We applied methods from network science and ecology to better understand the underlying structure of enteric co-infection among infants in two large longitudinal birth cohorts in Bangladesh. We used a configuration model to establish distributions of expected random co-occurrence, based on individual pathogen prevalence alone, for every pathogen pair among 30 enteropathogens detected by qRT-PCR in both diarrheal and asymptomatic stool specimens. We found two pairs, Enterotoxigenic E. coli (ETEC) with Enteropathogenic E. coli (EPEC), and ETEC with Campylobacter spp., co-infected significantly more than expected at random (both pairs co-occurring almost 4 standard deviations above what one could expect due to chance alone). Furthermore, we found a general pattern that bacteria-bacteria pairs appear together more frequently than expected at random, while virus-bacteria pairs tend to appear less frequently than expected based on model predictions. Finally, infants co-infected with leading bacteria-bacteria pairs had more days of diarrhea in the first year of life compared to infants without co-infection (p-value

Abstract Lysine methylation modulates the function of histone and non-histone proteins, and the enzymes that add or remove lysine methylation—lysine methyltransferases (KMTs) and lysine demethylases (KDMs), respectively—are frequently mutated and dysregulated in human diseases. Identification of lysine methylation sites proteome-wide has been a critical barrier to identifying the non-histone substrates of KMTs and KDMs and for studying functions of non-histone lysine methylation. Detection of lysine methylation by mass spectrometry (MS) typically relies on the enrichment of methylated peptides by pan-methyllysine antibodies. In this study, we use peptide microarrays to show that pan-methyllysine antibodies have sequence bias, and we evaluate how the differential selectivity of these reagents impacts the detection of methylated peptides in MS-based workflows. We discovered that most commercially available pan-Kme antibodies have an in vitro sequence bias, and multiple enrichment approaches provide the most comprehensive coverage of the lysine methylome. Overall, global lysine methylation proteomics with multiple characterized pan-methyllysine antibodies resulted in the detection of 5089 lysine methylation sites on 2751 proteins from two human cell lines, nearly doubling the number of reported lysine methylation sites in the human proteome.

Synchronously Amplified Photoacoustic Image Recovery (SAPhIRe) offers improved background suppression using non-linear properties of modulatable contrast agents. Using SAPhIRe, multiple contrast agents in the same absorption window can be detected independently based on their unique triplet-state lifetimes. Here, we have demonstrated the unmixing of rose bengal and eosin Y signals from solution based on triplet-state lifetime mapping using both fluorescence and photoacoustics. Varying the pump-probe delay enables resolution and recovery of fast-decaying rose bengal and of slowly decaying eosin Y modulated photoacoustic signals, resulting from optically gated triplet state residence. Distinct images were reconstructed within tissue-mimicking phantom using the fitting coefficients of triplet-state lifetimes. Fluorescence was used to screen for modulation prior to photoacoustic imaging. The results suggest that lifetime unmixing can be utilized to simultaneously detect multiple pathologies with overlapping spectra using photoacoustic imaging.

The health risks associated with wildfires are expected to increase due to climate change. Children are susceptible to wildfire smoke, but little is known about indoor smoke exposure at childcare facilities. The objective of this analysis was to estimate the effects of outdoor PM _2.5 and wildfire smoke episodes on indoor PM _2.5 at childcare facilities across British Columbia, Canada. We installed low-cost air-quality sensors inside and outside 45 childcare facilities and focused our analysis on operational hours (Monday–Friday, 08:00–18:00) during the 2022 wildfire season (01 August–31 October). Using random-slope random-intercept linear mixed effects regression, we estimated the overall and facility-specific effects of outdoor PM _2.5 on indoor PM _2.5 , while accounting for covariates. We examined how wildfire smoke affected this relationship by separately analyzing days with and without wildfire smoke. Average indoor PM _2.5 increased by 235% on wildfire days across facilities. There was a positive relationship between outdoor and indoor PM _2.5 that was not strongly influenced by linear adjustment for meteorological and area-based socio-economic factors. A 1.0 μ g m ^−3 increase in outdoor PM _2.5 was associated with a 0.55 μ g m ^−3 [95% CI: 0.47, 0.63] increase indoors on non-wildfire smoke days and 0.51 μ g m ^−3 [95% CI: 0.44, 0.58] on wildfire-smoke days. Facility-specific regression coefficients of the effect of outdoor PM _2.5 on indoor PM _2.5 was variable between facilities on wildfire (0.18–0.79 μ g m ^−3 ) and non-wildfire days (0.11–1.03 μ g m ^−3 ). Indoor PM _2.5 responded almost immediately to increased outdoor PM _2.5 concentrations. Across facilities, 89% and 93% of the total PM _2.5 infiltration over 60 min occurred within the first 10 min following an increase in outdoor PM _2.5 on non-wildfire and wildfire days, respectively. We found that indoor PM _2.5 in childcare facilities increased with outdoor PM _2.5 . This effect varied between facilities and between wildfire-smoke and non-wildfire smoke days. These findings highlight the importance of air quality monitoring at childcare facilities for informed decision-making.

Abstract Group A rotaviruses (RVA) remain a leading cause of pediatric diarrhea worldwide, in part due to underperformance of currently approved live-attenuated, oral vaccines in low-and-middle income countries. Improved immune correlates of protection (CoP) for existing oral vaccines and novel strategies to evaluate the performance of next-generation vaccines are needed. Use of oral vaccines as challenge agents in controlled human infection models is a potential approach to CoP discovery that remains underexplored. In a live-attenuated, oral rotavirus vaccine (Rotarix, GlaxoSmithKline) efficacy trial conducted among infants in Dhaka, Bangladesh, we explored the potential for the second dose of the two-dose series to be considered a challenge agent through which RVA immunity could be explored, using fecal virus shedding post-dose 2 as a marker of mucosal immunity. Among 180 vaccinated infants who completed the parent study per protocol, the absence of fecal vaccine shedding following the second dose of Rotarix suggested intestinal mucosal immunity generated by the first dose and a decreased risk of RVA diarrhea through 2 years of life (RR 0.616, 95% CI 0.392–0.968). Further development of controlled human infection models for group A rotaviruses, especially in prospective studies with larger sample sizes, may be a promising tool to assess rotavirus vaccine efficacy and CoPs.

Dengue virus causes a range of inflammatory pathology but understanding critical phases of the infection during human infection has been challenging. Here the author’s present immunotranscriptomic changes during the acute and clearance phases of a dengue virus serotype 2 human challenge model.

Background and AimsHigher total fruit and vegetable (FV) intakes have been associated with lower perceived stress. However, the relationship of FV intake with domains of perceived stress is unclear. The aim of this cross-sectional study was to explore the relationship between consumption of FV and four perceived stress domains (worries, tension, lack of joy and demands) in a population-based cohort of Australian adults.MethodsParticipants (n = 8,640) were men and women aged ≥25 years from the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. Dietary intake was assessed using a 74-item validated Food Frequency Questionnaire. Perceived stress domains were determined using a validated 20-item version of the Perceived Stress Questionnaire, with higher scores representing higher perceived stress. Cut-offs for high perceived stress domains were obtained from the highest quartiles of each domain for each sex. Multivariable-adjusted logistic regression was performed to investigate cross-sectional associations.ResultsThe mean age of participants (50.1% females) was 47.8 (SD 15) years. Those with higher intakes of FV, combined and separately, had a significantly lower odds (16–36%) for higher worries, tension and lack of joy, independent of other lifestyle factors.ConclusionIn Australian adults, higher consumption of FV was associated with lower odds of worries, tension and lack of joy. Following the dietary guidelines for the recommended intake of FV may help improve feelings of worries, tension and lack of joy, which are linked to mental health problems.

Nanostructured one-dimensional multiwall-carbon nanotubes have a variety of advantageous properties including good electrical conductivity and mechanical strength, and thus have been widely investigated for use in lithium-ion battery electrodes as conductive and microstructural additives, though they also possess some electrochemical activity. Their application to sodium-ion batteries has been less extensively researched, and therefore a greater understanding of the electrochemical reaction with sodium, and effects of slurry composition and electrolyte formulation is warranted, especially as these are likely components in future Na-ion electrode formulations. Here, we report the fabrication of aqueous and organic multi-wall carbon nanotube (MWCNT) negative electrodes processed by ball milling. The binder of choice is noted to greatly affect the electrochemical performance, both in terms of capacity retention and rate capability over a range of current densities from 25 to 500 mA g ^−1 . Switching from a carbonate- to diglyme-based electrolyte considerably improves initial coulombic efficiencies (∼10%–60%), attributed to less extensive formation of solid electrolyte interphase, and enables a reversible mechanism with capacities up to 150 mAh g ^−1 over 100 cycles depending upon the binder used. Ex-situ characterization of the discharged and cycled carbon nanotubes by powder x-ray diffraction, transmission electron microscopy and Raman spectroscopy provide an insight into how MWCNTs undergo sodiation and demonstrate a partially reversible structural transformation during cycling when using the diglyme-based electrolyte. This work lays the foundation for a better understanding of these versatile materials, especially when used in the most promising alternative energy storage technology to lithium ion.

Abstract Background The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes. Main text A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5′ adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence. Conclusions The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.

Background: Non-invasive screening for atherosclerosis or asymptomatic cardiovascular disease of the coronary and carotid arteries is commonly undertaken, and research has been focussed on how results from these screenings lead to behaviour change. However, no review has focused on the effects of these results on psychological distress and health-related quality of life (HRQoL). This protocol will outline how a scoping review will be conducted to map all available evidence on psychological distress and/or HRQoL outcomes following the provision of vascular imaging results of the coronary and carotid arteries. Methods: Arksey and O’Malley’s (2005) framework subsequently enhanced by Levac et al. (2010) and Peters et al (2015, 2017) will guide the scoping review. Databases such as MEDLINE (Clarivate), APA PsychINFO, EMBASE, Social Work Abstracts, Psychology and Behavioural Sciences Collection, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be searched using MeSH terms such as 'Coronary stenosis', 'Carotid Stenosis', 'Psychological Distress' and 'Quality of Life' and related terms. Two investigators will screen title and abstract and all articles meeting inclusion criteria will be extracted. Data on authors, publication year, country of origin, aims/purpose, methodology, intervention, outcome measures as well as key findings that relate to the scoping review questions will be extracted for each included study. The findings will be presented using tables and thematic narrative synthesis. The scoping review will not produce a pooled estimate of the impact of vascular imaging results on psychological distress and HRQoL but will present information from the included studies related to psychological distress and HRQoL. Conclusion: The review will highlight and address gaps in knowledge and provide direction for future investigations.

Background: Non-invasive screening for atherosclerosis or asymptomatic cardiovascular disease of the coronary and carotid arteries is commonly undertaken, and research has been focussed on how results from these screenings lead to behaviour change. However, no review has focused on the effects of these results on psychological distress and health-related quality of life (HRQoL). This protocol will outline how a scoping review will be conducted to map all available evidence on psychological distress and/or HRQoL outcomes following the provision of vascular imaging results of the coronary and carotid arteries. Methods: Arksey and O’Malley’s (2005) framework subsequently enhanced by Levac et al. (2010) and Peters et al (2015, 2017) will guide the scoping review. Databases such as MEDLINE (Clarivate), APA PsychINFO, EMBASE, Social Work Abstracts, Psychology and Behavioural Sciences Collection, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be searched using MeSH terms such as "Coronary stenosis", "Carotid Stenosis", "Psychological Distress" and "Quality of Life" and related terms. Two investigators will screen title and abstract and all articles meeting inclusion criteria will be extracted. Data on authors, publication year, country of origin, aims/purpose, methodology, intervention, outcome measures as well as key findings that relate to the scoping review questions will be extracted for each included study. The findings will be presented using tables and thematic narrative synthesis. The scoping review will not produce a pooled estimate of the impact of vascular imaging results on psychological distress and HRQoL but will present information from the included studies related to psychological distress and HRQoL. Conclusion: The review will highlight and address gaps in knowledge and provide direction for future investigations.

Background: Non-invasive screening for atherosclerosis or asymptomatic cardiovascular disease of the coronary and carotid arteries is commonly undertaken, and research has been focussed on how results from these screenings lead to behaviour change. However, no review has focused on the effects of these results on psychological distress and health-related quality of life (HRQoL). This protocol will outline how a scoping review will be conducted to map all available evidence on psychological distress and/or HRQoL outcomes following the provision of vascular imaging results of the coronary and carotid arteries. Methods: Arksey and O’Malley’s (2005) framework subsequently enhanced by Levac et al. (2010) and Peters et al (2015, 2017) will guide the scoping review. Databases such as MEDLINE (Clarivate), APA PsychINFO, EMBASE, Social Work Abstracts, Psychology and Behavioural Sciences Collection, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be searched using MeSH terms such as 'Coronary stenosis', 'Carotid Stenosis', 'Psychological Distress' and 'Quality of Life' and related terms. Two investigators will screen title and abstract and all articles meeting inclusion criteria will be extracted. Data on authors, publication year, country of origin, aims/purpose, methodology, intervention, outcome measures as well as key findings that relate to the scoping review questions will be extracted for each included study. The findings will be presented using tables and thematic narrative synthesis. The scoping review will not produce a pooled estimate of the impact of vascular imaging results on psychological distress and HRQoL but will present information from the included studies related to psychological distress and HRQoL. Conclusion: The review will highlight and address gaps in knowledge and provide direction for future investigations.

Abstract Relationship‐based medical care is essential in the management of chronic pain. Opioids are often ineffective and can cause significant harm. However, there is significant time pressure, and there are insufficient resources and guidelines for GPs to be able to offer alternatives, putting the NHS at risk of a growing opioid epidemic.

Background: Non-invasive screening for atherosclerosis or asymptomatic cardiovascular disease of the coronary and carotid arteries is commonly undertaken, and research has been focussed on how results from these screenings lead to behaviour change. However, no review has focused on the effects of these results on mental distress and quality of life. This protocol will outline how a scoping review will be conducted to map all available evidence on mental distress or quality of life outcomes following the provision of vascular imaging results of the coronary and carotid arteries. Methods: Arksey and O’Malley’s (2005) framework will guide the scoping review. Databases such as MEDLINE (Clarivate), APA PsychINFO, EMBASE, Social Work Abstracts, Psychology and Behavioural Sciences Collection, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be searched using MeSH terms such as 'Coronary stenosis', 'Carotid Stenosis', 'Psychological Distress' and 'Quality of Life' and related terms. Two investigators will screen title and abstract and all articles meeting inclusion criteria will be extracted. Data on authors, publication year, country of origin, aims/purpose, methodology, intervention, outcome measures as well as key findings that relate to the scoping review questions will be extracted for each included study. The findings will be presented using tables and thematic narrative synthesis. The scoping review will not produce a pooled estimate of the impact of vascular imaging results on mental distress and quality of life but will present information from the included studies related to mental distress and QOL. Conclusion: The review will highlight and address gaps in knowledge and provide direction for future investigations.

In molecular and cellular photoacoustic imaging with exogenous contrast agents, image contrast is plagued by background resulting from endogenous absorbers in tissue. By using optically modulatable nanoparticles, we develop ultra-sensitive photoacoustic imaging by rejecting endogenous background signals and drastically improving signal contrast through time-delayed pump-probe pulsed laser illumination. Gated by prior pump excitation, modulatable photoacoustic (mPA) signals are recovered from unmodulatable background through simple, real-time image processing to yield background-free photoacoustic signal recovery within tissue mimicking phantoms and from ex-vivo tissues. Inherently multimodal, the fluorescence and mPA sensitivity improvements demonstrate the promise of Synchronously Amplified Photoacoustic Image Recovery (SAPhIRe) for PA imaging in diagnosis and therapy.

Background: Home self-monitoring of blood pressure is widely used in primary care to assist in the diagnosis of hypertension, as well as to improve clinical outcomes and support adherence to medication. The National Institute for Health and Care Excellence (NICE) care pathways for hypertension recommend specific guidelines, although they lack detail on supporting patients to self-monitor. Aim: To elicit primary care practitioners’ experiences of managing patients’ home blood pressure self-monitoring, across surgeries located in different socioeconomic areas. Design & setting: A qualitative focus group study was conducted with a total of 21 primary care professionals. Method: Participants were GPs and practice nurses (PNs), purposively recruited from surgeries in areas of low and high deprivation, according to the English indices of multiple deprivation. Six vignettes were developed featuring data from interviews with people who self-monitor and these were used in five focus groups. Results were thematically analysed. Results: Themes derived in the thematic analysis largely reflected topics covered by the vignettes. These included: advice on purchase of a device; supporting home monitoring; mitigating patient anxiety experienced as a result of home monitoring; valuing patients’ data; and effect of socioeconomic factors. Conclusion: The work provides an account of methods used by primary care practitioners in the management of home blood pressure self-monitoring, where guidance may be lacking and primary care practitioners act on their own judgement. Findings complement recent policy documentation, which recognises the need to adopt new ways of working to empower patients (for example, additional support from healthcare assistants), but lacks detail on how this should be done.

The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, binds the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. Following an in-silico derived hypothesis we found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate an activation mechanism where the n-aniline ring of fentanyl mediates μOR β-arrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.

We describe the mathematical transformations required to convert the data recorded using typical 6-axis microelectromechanical systems (MEMS) sensor packages (3-axis rate gyroscopes and 3-axis accelerometers) when attached to an object undergoing a short duration loading event, such as blast loading, where inertial data alone are sufficient to track the object motion. By using the quaternion description, the complex object rotations and displacements that typically occur are translated into the more convenient earth frame of reference. An illustrative example is presented where a large and heavy object was thrown by the action of a very strong air blast in a complex manner. The data conversion process yielded an accurate animation of the object’s subsequent motion.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.

Objective: Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects β-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP-1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands. Methods: Using primary mouse islets and the β-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using a fluorescein-tagged exendin-4 and GFP-tagged GLP-1R. Results: Rodent β-cells chronically exposed to high glucose had diminished responses to GLP-1R agonists including: diminished insulin secretory response; reduced phosphorylation of (CREB); impaired cAMP response, attributable to chronically increased cAMP levels. GLP-1R signaling systems were affected by hyperglycemia with increased expression of mRNAs encoding the inducible cAMP early repressor (ICER) and adenylyl cyclase 8, reduced PKA activity due to increased expression of the PKA-RIα subunit, reduced GLP-1R mRNA expression and loss of GLP-1R from the cell surface. To specifically examine the loss of GLP-1R from the plasma membrane a GLP-1R-GFP fusion protein was employed to visualize subcellular localization. Under low glucose conditions or when PKA activity was inhibited, GLP-1R-GFP was found at the plasma membrane. Conversely high glucose, expression of a constitutively active PKA subunit, or exposure to exendin-4 or forskolin led to GLP-1R-GFP internalization. Mutation of serine residue 301 of the GLP-1R abolished the glucose-dependent loss of the receptor from the plasma membrane. This was associated with a loss of an interaction between the receptor and the small ubiquitin-related modifier (SUMO), an interaction that was found to be necessary for internalization of the receptor. Conclusions: These data show that glucose acting, at least in part, via PKA leads to the loss of the GLP-1R from the cell surface and an impairment of GLP-1R signaling, which may underlie the reduced clinical efficacy of GLP-1R based therapies in individuals with poorly controlled hyperglycemia.