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This retrospective population-based analysis assessed variations in urgent healthcare use by children and young people (CYP) across UK nations (England, Scotland and Wales) between 2007 and 2017. The study focused on urgent hospital admissions, short stay urgent admissions (SSUA) and Emergency Department (ED) attendances among CYP aged <25 years, stratified by age groups and Index of Multiple Deprivation (IMD) quintile groups. A linear mixed model was used to assess trends in healthcare activity over time and across deprivation quintiles. Urgent admissions, SSUA and ED attendances increased across all deprivation quintiles in all studied nations. Increasing deprivation was consistently associated with higher urgent healthcare utilisation. In England, the rise in urgent admissions and SSUA for CYP was slower for CYP from the quintile of greatest deprivation compared those from the least deprived quintile (respective mean differences 0.69/1000/y [95% CI 0.53, 0.85] and 0.25/1000/y [0.07, 0.42]), leading to a narrowing in health inequality. Conversely, in Scotland, urgent admissions and SSUA increased more rapidly for CYP from all deprivation quintiles, widening health inequality. Understanding the differences we describe here could inform changes to NHS pathways of care across the UK which slow the rise in urgent healthcare use for CYP. [ABSTRACT FROM AUTHOR]

Background: Parotidectomies are indicated for a variety of reasons. Regardless of the indication for surgery, facial reanimation may be required because of facial nerve sacrifice or iatrogenic damage. In these cases, facial restoration performed concurrently with ablative surgery is considered the gold standard, and delayed reanimation is usually not attempted. Methods: A retrospective review of all patients who underwent parotidectomies from 2009 to 2022 in a single institution was performed. Indications, surgical techniques, and outcomes of an algorithmic template were applied to these cases using the Sunnybrook, Terzis scores, and Smile Index. A comparison was made between immediate vs. late repairs. Results: Of a total of 90 patients who underwent parotidectomy, 17 (15.3%) had a radical parotidectomy, and 73 (84.7%) had a total or superficial parotidectomy. Among those who underwent complete removal of the gland and nerve sacrifice, eight patients (47.1%) had facial restoration. There were four patients each in the immediate (n = 4) and late repair (n = 4) groups. Surgical techniques ranged from cable grafts to vascularized cross facial nerve grafts (sural communicating nerve flap as per the Koshima procedure) and vascularized nerve flaps (chimeric vastus lateralis and anterolateral thigh flaps, and superficial circumflex perforator flap with lateral femoral cutaneous nerve). Conclusions: The algorithm between one technique and another should take into consideration age, comorbidities, soft tissue defects, presence of facial nerve branches for reinnervation, and donor site morbidity. While immediate facial nerve repair is ideal, there is still benefit in performing a delayed repair in this algorithm. [ABSTRACT FROM AUTHOR]

Many commentators have suggested that the first 18 months of the Johnson government were characterised by a propensity to centralise power. However, few accounts have situated the administration in the historical context of the British state or systematically examined these centralising tendencies. This article attempts to address these omissions. First, through a critical assessment of the literature on authoritarian neoliberalism, the concept of 'executive centralisation' is developed within the context of the British state. Second, the article applies this revised framework to the early stages of the Johnson government. While a dominant executive is a long-standing feature of the British political system, it is argued that Johnson has pursued a multifaceted centralisation strategy facilitated by the context of Brexit and COVID-19. In identifying the role of consent in this process, the article augments scholarship on 'authoritarian neoliberalism' as a moment in neoliberal governance characterised by the ascendance of coercive governing strategies. [ABSTRACT FROM AUTHOR]

The genomes of positive-sense RNA viruses encode polyproteins that are essential for mediating viral replication. These viral polyproteins must undergo proteolysis (also termed polyprotein processing) to generate functional protein units. This proteolysis can be performed by virally-encoded proteases as well as host cellular proteases, and is generally believed to be a key step in regulating viral replication. Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis. The positive-sense RNA genome is translated to generate a polyprotein, termed pORF1, which is necessary and sufficient for viral genome replication. However, the mechanism of polyprotein processing in HEV remains to be determined. In this study, we aimed to understand processing of this polyprotein and its role in viral replication using a combination of in vitro translation experiments and HEV sub-genomic replicons. Our data suggest no evidence for a virally-encoded protease or auto-proteolytic activity, as in vitro translation predominantly generates unprocessed viral polyprotein precursors. However, seven cleavage sites within the polyprotein (suggested by bioinformatic analysis) are susceptible to the host cellular protease, thrombin. Using two sub-genomic replicon systems, we demonstrate that mutagenesis of these sites prevents replication, as does pharmacological inhibition of serine proteases including thrombin. Overall, our data supports a model where HEV uses host proteases to support replication and could have evolved to be independent of a virally-encoded protease for polyprotein processing. Author summary: Positive-strand RNA viruses produce polyproteins that are cleaved by proteases that control viral replication. The polyproteins of all well studied positive-strand viruses undergo proteolysis in a highly controlled manner to generate functional proteins and regulate the transition from translation to RNA replication. Proteolysis of viral polyproteins is generally performed by virally-encoded proteases, although host cellular proteases are used by some viruses. In this report, we provide evidence that suggests that hepatitis E virus, a medically important human pathogen, does not encode a protease and unlike other viral polyproteins, cannot undergo auto-catalytic processing. Instead, we provide evidence that the polyprotein is susceptible to proteolysis by host cell protease thrombin and that this is essential for viral replication. Our data contradict the previous dogma of positive-sense viral replication and suggests a model where this virus could have evolved to use a host protease to control viral replication and tropism. [ABSTRACT FROM AUTHOR]

DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely. DNA repair defects underlie many cancer syndromes. This study investigates whether parents with inherited problems of DNA repair pass on an increased number of de novo mutations to their children. The authors find that this does occur, but that clinical consequences are unlikely. [ABSTRACT FROM AUTHOR]

DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely. DNA repair defects underlie many cancer syndromes. This study investigates whether parents with inherited problems of DNA repair pass on an increased number of de novo mutations to their children. The authors find that this does occur, but that clinical consequences are unlikely. [ABSTRACT FROM AUTHOR]

DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely. DNA repair defects underlie many cancer syndromes. This study investigates whether parents with inherited problems of DNA repair pass on an increased number of de novo mutations to their children. The authors find that this does occur, but that clinical consequences are unlikely. [ABSTRACT FROM AUTHOR]

The dolabellane‐type diterpene dictyoxetane represents a significant challenge to synthetic organic chemistry. Methodology directed towards the total synthesis of naturally occurring (+)‐dictyoxetane is reported. Catalytic asymmetric synthesis of the trans‐hydrindane ring system is achieved through chemoselective deoxygenation of the Hajos‐Parrish ketone. An alternative to the Garst‐Spencer furan annulation is developed for the synthesis of a 2,5‐dimethyl, tetrasubstituted furan, employing a tandem 5‐exo‐dig alcohol to alkyne cyclisation/aromatisation reaction as a key step. The (4+3) cycloaddition reaction of an oxyallyl cation with a tetrasubstituted furan is established on a cyclohexanone‐derived model system, and a range of related (4+3) cycloadditions investigated on a homochiral, trans‐hydrindane‐fused furan, where regio‐ and diastereoselectivity is required for the natural product synthesis. In an alternative (4+2) Diels‐Alder approach, a C2‐symmetric vinyl sulfoxide‐based chiral ketene equivalent is used to prepare oxanorbornenes with the same oxygen bridge stereochemistry found in the 2,7‐dioxatricyclo[4.2.1.03,8]nonane ring system of the natural product. [ABSTRACT FROM AUTHOR]

Left–right asymmetries in the nervous system (lateralisation) influence a broad range of behaviours, from social responses to navigation and language. The role and pathways of endogenous and environmental mechanisms in the ontogeny of lateralisation remains to be established. The domestic chick is a model of both endogenous and experience-induced lateralisation driven by light exposure. Following the endogenous rightward rotation of the embryo, the asymmetrical position in the egg results in a greater exposure of the right eye to environmental light. To identify the genetic pathways activated by asymmetric light stimulation, and their time course, we exposed embryos to different light regimes: darkness, 6 h of light and 24 h of light. We used RNA-seq to compare gene expression in the right and left retinas and telencephalon. We detected differential gene expression in right vs left retina after 6 h of light exposure. This difference was absent in the darkness condition and had already disappeared by 24 h of light exposure, suggesting that light-induced activation is a self-terminating phenomenon. This transient effect of light exposure was associated with a downregulation of the sensitive-period mediator gene DIO2 (iodothyronine deiodinase 2) in the right retina. No differences between genes expressed in the right vs. left telencephalon were detected. Gene networks associated with lateralisation were connected to vascularisation, cell motility, and the extracellular matrix. Interestingly, we know that the extracellular matrix—including the differentially expressed PDGFRB gene—is involved in morphogenesis, sensitive periods, and in the endogenous chiral mechanism of primary cilia, that drives lateralisation. Our data show a similarity between endogenous and experience-driven lateralisation, identifying functional gene networks that affect lateralisation in a specific time window. [ABSTRACT FROM AUTHOR]

Non-coding regions of viral RNA (vRNA) genomes are critically important in the regulation of gene expression. In particular, pseudoknot (PK) structures, which are present in a wide range of RNA molecules, have a variety of roles. The 5′ untranslated region (5′ UTR) of foot-and-mouth disease virus (FMDV) vRNA is considerably longer than in other viruses from the picornavirus family and consists of a number of distinctive structural motifs that includes multiple (2, 3 or 4 depending on the virus strain) putative PKs linked in tandem. The role(s) of the PKs in the FMDV infection are not fully understood. Here, using bioinformatics, sub-genomic replicons and recombinant viruses we have investigated the structural conservation and importance of the PKs in the FMDV lifecycle. Our results show that despite the conservation of two or more PKs across all FMDVs, a replicon lacking PKs was replication competent, albeit at reduced levels. Furthermore, in competition experiments, GFP FMDV replicons with less than two (0 or 1) PK structures were outcompeted by a mCherry FMDV wt replicon that had 4 PKs, whereas GFP replicons with 2 or 4 PKs were not. This apparent replicative advantage offered by the additional PKs correlates with the maintenance of at least two PKs in the genomes of FMDV field isolates. Despite a replicon lacking any PKs retaining the ability to replicate, viruses completely lacking PK were not viable and at least one PK was essential for recovery of infections virus, suggesting a role for the PKs in virion assembly. Thus, our study points to roles for the PKs in both vRNA replication and virion assembly, thereby improving understanding the molecular biology of FMDV replication and the wider roles of PK in RNA functions. Author summary: Foot-and-mouth disease (FMD) is a highly contagious viral disease posing a constant threat to the global livestock industry, as it remains endemic in many parts of the world. The development of novel control measures for FMD could have major economic and social value worldwide, however, this will require a deeper understanding of the molecular mechanisms of FMDV replication. A number of features of the viral RNA genome remain poorly understood, including the role of a series of putative pseudoknot (PK) structures, where the RNA is predicted to fold back on itself. In this study, we confirmed the conservation and structure of these PKs in the FMDV genome and showed that the presence of at least one is essential for production of infectious virus particles. However, the presence of two or more PKs was advantageous in replication competition experiments. These results correlate with the observation that genomes of all known FMDV field isolates include at least two PK structures. We suggest roles for the PKs in both replication and virion assembly. [ABSTRACT FROM AUTHOR]

The paper deals with the problem of extrapolating data derived from sampling a C m function at scattered sites on a Lipschitz region Ω in R d to points outside of Ω in a computationally efficient way. While extrapolation problems go back to Whitney and many such problems have had successful theoretical resolutions, practical, computationally efficient implementations seem to be lacking. The goal here is to provide one way of obtaining such a method in a solid mathematical framework. The method utilized is a novel two-step moving least squares procedure (MLS) where the second step incorporates an error term obtained from the first MLS step. While the utility of the extrapolation degrades as a function of the distance to the boundary of Ω , the method gives rise to improved meshfree approximation error estimates when using the local Lagrange kernels related to certain radial basis functions. [ABSTRACT FROM AUTHOR]

Despite the outpouring of scholarship on the motivations behind the 2016 EU referendum result and the preliminary impact of Brexit on British politics, comparatively little time has been spent analysing the government(s) entrusted with implementation. This article aims to address this gap in the literature, examining government management of the Brexit process as a case study through which to illustrate the continued relevance of the British Political Tradition in British politics. It argues that through Brexit implementation, the May government initiated a process of centralisation of both policy-making influence and administrative resources within Whitehall. This process was shielded externally by appeals to the referendum result as an imperative mandate parliament was obliged to implement. Although the political landscape of May's premiership was characterised by flux, these internal shifts towards centralisation in the executive are proposed to have had a more sustained impact through the reassertion of aspects of Britain's 'power-hoarding' constitutional settlement. [ABSTRACT FROM AUTHOR]

Objective: To undertake a systematic review of reviews of the prevalence of symptoms and signs of COVID-19 in those aged under 20 years.Design: Narrative systematic review of reviews. PubMed, medRxiv, Europe PMC and COVID-19 Living Evidence Database were searched on 9 October 2020.Setting: All settings, including hospitalised and community settings.Patients: Children and young people (CYP) under age 20 years with laboratory-proven COVID-19.Study Review, Data Extraction and Quality: Potentially eligible articles were reviewed on title and abstract by one reviewer. Quality was assessed using the modified AMSTARS criteria and data were extracted from included studies by two reviewers.Main Outcome Measures: Prevalence of symptoms and signs of COVID-19.Results: 1325 studies were identified and 18 reviews were included. Eight were high quality, 7 medium and 3 low quality. All reviews were dominated by studies of hospitalised children. The proportion of asymptomatic CYP ranged from 14.6% to 42%. Fever and cough were the the most common symptoms; proportions with fever ranged from 46% to 64.2% and with cough from 32% to 55.9%. All other symptoms or signs including rhinorrhoea, sore throat, headache, fatigue/myalgia and gastrointestinal symptoms including diarrhoea and vomiting were infrequent, occurring in less than 10%-20%.Conclusions: Fever and cough are the most common symptoms in CYP with COVID-19, with other symptoms infrequent. Further research on symptoms in community samples are needed to inform pragmatic identification and testing programmes for CYP. [ABSTRACT FROM AUTHOR]

Dimensions of character are often overlooked in professional practice at the expense of the development of technical competence and operational efficiency. Drawing on philosophical accounts of virtue ethics and positive psychology, the present work attempts to elevate the role of 'good' character in the professional domain. A 'good' professional is ideally one that exemplifies dimensions of character informed by sound judgement. A total of 2340 professionals, from five discrete professions, were profiled based on their valuation of qualities pertaining to character and judgement. Profile differences were subsequently examined in the self-reported experience of professional purpose towards a wider societal 'good'. Analysis of covariance, controlling for stage of career, revealed that professionals valuing character reported higher professional purpose than those overweighting the importance of judgement or valuing neither character nor judgement, F(3, 2054) = 7.92, p <.001. No differences were found between the two groups valuing character, irrespective of whether judgement was valued simultaneously. This profiling analysis of entry-level and in-service professionals, based on their holistic character composition, paves the way for fresh philosophical discussion regarding what constitutes a 'good' professional and the interplay between character and judgement. The empirical findings may be of substantive value in helping to recognise how the dimensions of character and judgement may impact upon practitioners' professional purpose. [ABSTRACT FROM AUTHOR]

Objective: To compare cause-specific UK mortality in children and young people (CYP) with EU15+ countries (European Union countries pre-2004, Australia, Canada and Norway).Design: Mortality estimates were coded from the WHO World Mortality Database. Causes of death were mapped using the Global Burden of Disease mortality hierarchy to 22 cause groups. We compared UK mortality by cause, age group and sex with EU15+ countries in 2015 (or latest available) using Poisson regression models. We then ranked the UK compared with the EU15+ for each cause.Setting: The UK and EU15+ countries.Participants: CYP aged 1-19.Main Outcome Measure: Mortality rate per 100 000 and number of deaths.Results: UK mortality in 2015 was significantly higher than the EU15+ for common infections (both sexes aged 1-9, boys aged 10-14 and girls aged 15-19); chronic respiratory conditions (both sexes aged 5-14); and digestive, neurological and diabetes/urological/blood/endocrine conditions (girls aged 15-19). UK mortality was significantly lower for transport injuries (boys aged 15-19). The UK had the worst to third worst mortality rank for common infections in both sexes and all age groups, and in five out of eight non-communicable disease (NCD) causes in both sexes in at least one age group. UK mortality rank for injuries in 2015 was in the top half of countries for most causes.Conclusions: UK CYP mortality is higher than a group of comparable countries for common infections and multiple NCD causes. Excess UK CYP mortality may be amenable to health system strengthening. [ABSTRACT FROM AUTHOR]

Background: The amyloid cascade hypothesis of Alzheimer's disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown.Objective: Here, we aimed to investigate astrocyte-related pathological changes of Aβ and AβPP using immunohistochemistry and biochemical studies in both animal and cell models.Methods/results: We utilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1.Conclusion: Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD. [ABSTRACT FROM AUTHOR]

The care of any wound in the community requires multidisciplinary working between healthcare professionals. In this article, the authors offer five generalisable principles that colleagues providing community care can apply in order to achieve timely wound healing: (1) assessment and exclusion of disease processes; (2) wound cleansing; (3) timely dressing change; (4) appropriate (dressing choice; and (5) considered antibiotic prescription. High-quality wound care is an essential aspect of healthcare practice but lacks an evidence base and standardised practice at present. The practice and teaching of wound care should be more greatly emphasised in healthcare training for all disciplines. [ABSTRACT FROM AUTHOR]

We describe a novel meshless Galerkin method for numerically solving semilinear parabolic equations on spheres. The new approximation method is based upon a discretization in space using spherical basis functions in a Galerkin approximation. As our spatial approximation spaces are built with spherical basis functions, they can be of arbitrary order and do not require the construction of an underlying mesh. We will establish convergence of the meshless method by adapting, to the sphere, a convergence result due to Thomée and Wahlbin. To do this requires proving new approximation results, including a novel inverse or Nikolskii inequality for spherical basis functions. We also discuss how the integrals in the Galerkin method can accurately and more efficiently be computed using a recently developed quadrature rule. These new quadrature formulas also apply to Galerkin approximations of elliptic partial differential equations on the sphere. Finally, we provide several numerical examples. [ABSTRACT FROM AUTHOR]

RNA aptamers are synthetic single stranded RNA oligonucleotides that function analogously to antibodies. Recently, they have shown promise for use in treating inflammatory skin disease as, unlike antibody-based biologics, they are able to enter the skin following topical administration. However, it is important to understand the inflammatory milieu into which aptamers are delivered, as numerous immune-modulating mediators will be present at abnormal levels. LL-37 is an important immune-modifying protein upregulated in several inflammatory skin conditions, including psoriasis, rosacea and eczema. This inflammatory antimicrobial peptide is known to complex nucleic acids and induce both inflammatory and interferon responses from keratinocytes. Given the attractive notion of using RNA aptamers in topical medication and the prevalence of LL-37 in these inflammatory skin conditions, we examined the effect of LL-37 on the efficacy and safety of the anti-IL-17A RNA aptamer, Apt 21-2. LL-37 was demonstrated to complex with the RNA aptamer by electrophoretic mobility shift and filter binding assays. In contrast to free Apt 21-2, LL-37-complexed Apt 21-2 was observed to efficiently enter both keratinocytes and fibroblasts by confocal microscopy. Despite internalization of LL-37-complexed aptamers, measurement of inflammatory mediators and interferon stimulated genes showed LL-37-complexed Apt 21-2 remained immunologically inert in keratinocytes, fibroblasts, and peripheral blood mononuclear cells including infiltrating dendritic cells and monocytes. The findings of this study suggest RNA aptamers delivered into an inflammatory milieu rich in LL-37 may become complexed and subsequently internalized by surrounding cells in the skin. Whilst the results of this study indicate delivery of RNA aptamers into tissue rich in LL-37 should not cause an unwarranted inflammatory of interferon response, these results have significant implications for the efficacy of aptamers with regards to extracellular vs. intracellular targets that should be taken into consideration when developing treatment strategies utilizing RNA aptamers in inflamed tissue. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is a re-emerging Alphavirus causing fever, joint pain, skin rash, arthralgia, and occasionally death. Antiviral therapies and/or effective vaccines are urgently required. CHIKV biology is poorly understood, in particular the functions of the non-structural protein 3 (nsP3). Here we present the results of a mutagenic analysis of the alphavirus unique domain (AUD) of nsP3. Informed by the structure of the Sindbis virus AUD and an alignment of amino acid sequences of multiple alphaviruses, a series of mutations in the AUD were generated in a CHIKV sub-genomic replicon. This analysis revealed an essential role for the AUD in CHIKV RNA replication, with mutants exhibiting species- and cell-type specific phenotypes. To test if the AUD played a role in other stages of the virus lifecycle, the mutants were analysed in the context of infectious CHIKV. This analysis indicated that the AUD was also required for virus assembly. In particular, one mutant (P247A/V248A) exhibited a dramatic reduction in production of infectious virus. This phenotype was shown to be due to a block in transcription of the subgenomic RNA leading to reduced synthesis of the structural proteins and a concomitant reduction in virus production. This phenotype could be further explained by both a reduction in the binding of the P247A/V248A mutant nsP3 to viral genomic RNA in vivo, and the reduced affinity of the mutant AUD for the subgenomic promoter RNA in vitro. We propose that the AUD is a pleiotropic protein domain, with multiple functions during CHIKV RNA synthesis. [ABSTRACT FROM AUTHOR]

Objective To investigate if socioeconomic gradients in health reduce during adolescence (the equalisation hypothesis) in four low-income and middle-income countries (LMIC). setting Analysis of the Young Lives Study cohorts in Ethiopia, Peru, Vietnam and India. Participants A total of 3395 participants (across the four cohorts) aged 6-10 years at enrolment and followed up for 11 years. Outcomes measured Change in income-related health inequalities from mid-childhood to late adolescence. Socioeconomic status was determined by wealth index quartile. The health indicators included were self-reported health, injuries in the previous 4 years, presence of long-term health problems, low mood, alcohol use, overweight/obesity, thinness and stunting. The relative risk of each adverse health outcome between highest and lowest wealth index quartile were compared across four waves of the study within each country. results We found steep socioeconomic gradients across multiple health indicators in all four countries. Socioeconomic gradients remained similar across all waves of the study, with no significant decrease during adolescence. Conclusion We found no consistent evidence of equalisation for income-related health inequalities in youth in these LMIC. Socioeconomic gradients for health in these cohorts appear to persist and be equally damaging across the early life course and during adolescence. [ABSTRACT FROM AUTHOR]

Background: The Countdown for UK Child Survival tracks recent UK child mortality trends and makes recommendations for improvement.Methods: We used data from the WHO World Mortality Database to calculate mortality from 1970 to 2014 for 0-19 year olds in the UK and a comparable group of wealthy countries (the EU15+). We used Poisson regression models to assess the significance of apparent differences. We extrapolated model coefficients to estimate future disparites between the UK and the EU15+ to 2030. We proposed goals and intermediate indicators to track UK mortality in keeping with the UN Sustainable Development Goals.Results: UK infant mortality continues to track in the worst decile of EU15+ mortality with 1-4 year mortality in the worst quartile. Annual reductions in total UK mortality have been significantly lower than the EU15+ since 1990 for infant, postneonatal and 1-4 year mortality. If current trends persist, by 2030 UK infant mortality and 1-4 year mortality could be respectively 180% and 145% of EU15+ median mortality. UK non-communicable disease (NCD) mortality among 1-4 years and 15-19 years persists in the worst quartile. UK injury mortality continues in the best quartile. A framework of goals and indicators for UK child survival and health is presented.Discussion: UK mortality among under 10 years of age continues to diverge from the EU15+ median, and UK NCD mortality remains persistently poor. We propose a set of goals to improve UK childhood survival by 2030 and an annual Countdown mechanism to monitor progress towards these targets. [ABSTRACT FROM AUTHOR]

Painful neuropathy (PN) is a prevalent condition in patients with metabolic syndrome (MetS). However, the pathogenic mechanisms of metabolic syndrome-associated painful neuropathy (MetSPN) remain unclear. In the current study, high-fat-fed mice (HF mice) were used to study MetSPN. HF mice developed MetS phenotypes, including increased body weight, elevated plasma cholesterol levels, and insulin resistance in comparison with control-fat-fed (CF) mice. Subsequently, HF mice developed mechanical allodynia and thermal hyperalgesia in hind paws after 8 wk of diet treatment. These pain behaviors coincided with increased densities of nociceptive epidermal nerve fibers and inflammatory cells such as Langerhans cells and macrophages in hind paw skin. To study the effect of MetS on profiles of cytokine expression in HF mice, we used a multiplex cytokine assay to study the protein expression of 12 pro-inflammatory and anti-inflammatory cytokines in dorsal root ganglion and serum samples. This method detected the elevated levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, and interleukin (IL)-6, IL-1β as well as reduced anti-inflammatory IL-10 in lumbar dorsal root ganglia (LDRG) of HF mice. Intraperitoneal administration of IL-10 reduced the upregulation of pro-inflammatory cytokines and alleviated pain behaviors in HF mice without affecting MetS phenotypes. Our findings suggested targeting HF-induced cytokine dysregulation could be an effective strategy for treating MetSPN. [ABSTRACT FROM AUTHOR]

Introduction: Life-course studies are needed to explore how exposures during adolescence, particularly puberty, contribute to later cardiovascular risk and cognitive health in low and middle-income countries (LMIC), where 90% of the world’s young people live. The extent of any existing cohorts investigating these outcomes in LMIC has not previously been described. Methods: We performed a systematic literature review to identify population cohort studies of adolescents in LMIC that assessed anthropometry and any of cardiovascular risk (blood pressure, physical activity, plasma glucose/lipid profile and substance misuse), puberty (age at menarche, Tanner staging, or other form of pubertal staging) or cognitive outcomes. Studies that recruited participants on the basis of a pre-existing condition or involved less than 500 young people were excluded. Findings: 1829 studies were identified, and 24 cohorts fulfilled inclusion criteria based in Asia (10), Africa (6) and South / Central America (8). 14 (58%) of cohorts identified were based in one of four countries; India, Brazil, Vietnam or Ethiopia. Only 2 cohorts included a comprehensive cardiovascular assessment, tanner pubertal staging, and cognitive outcomes. Conclusion: Improved utilisation of existing datasets and additional cohort studies of adolescents in LMIC that collect contemporaneous measures of growth, cognition, cardiovascular risk and pubertal development are needed to better understand how this period of the life course influences future non-communicable disease morbidity and cognitive outcomes. [ABSTRACT FROM AUTHOR]

The RNA genomes of picornaviruses are translated into single polyproteins which are subsequently cleaved that into structural and non-structural protein products. For genetic economy, proteins and processing intermediates have evolved to perform distinct functions. The picornavirus precursor protein, P3, is cleaved to produce membrane-associated 3A, primer peptide 3B, protease 3Cpro and polymerase 3Dpol. Uniquely, foot-and-mouth disease virus (FMDV) encodes three similar copies of 3B (3B1-3), thus providing a convenient natural system to explore the role(s) of 3B in the processing cascade. Using a replicon system, we confirmed by genetic deletion or functional inactivation that each copy of 3B appears to function independently to prime FMDV RNA replication. However, we also show that deletion of 3B3 prevents replication and that this could be reversed by introducing mutations at the C-terminus of 3B2 that restored the natural sequence at the 3B3-3C cleavage site. In vitro translation studies showed that precursors with 3B3 deleted were rapidly cleaved to produce 3CD but that no polymerase, 3Dpol, was detected. Complementation assays, using distinguishable replicons bearing different inactivating mutations, showed that replicons with mutations within 3Dpol could be recovered by 3Dpol derived from “helper” replicons (incorporating inactivation mutations in all three copies of 3B). However, complementation was not observed when the natural 3B-3C cleavage site was altered in the “helper” replicon, again suggesting that a processing abnormality at this position prevented the production of 3Dpol. When mutations affecting polyprotein processing were introduced into an infectious clone, viable viruses were recovered but these had acquired compensatory mutations in the 3B-3C cleavage site. These mutations were shown to restore the wild-type processing characteristics when analysed in an in vitro processing assay. Overall, this study demonstrates a dual functional role of the small primer peptide 3B3, further highlighting how picornaviruses increase genetic economy. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions. [ABSTRACT FROM AUTHOR]

Background: Income inequality and national wealth are strong determinants for health, but few studies have systematically investigated their influence on mortality across the early life-course, particularly outside the high-income world.Methods: We performed cross-sectional regression analyses of the relationship between income inequality (national Gini coefficient) and national wealth (Gross Domestic Product (GDP) averaged over previous decade), and all-cause and grouped cause national mortality rate amongst infants, 1-4, 5-9, 10-14, 15-19 and 20-24 year olds in low and middle-income countries (LMIC) in 2012. Gini models were adjusted for GDP.Results: Data were available for 103 (79%) countries. Gini was positively associated with increased all-cause and communicable disease mortality in both sexes across all age groups, after adjusting for national wealth. Gini was only positively associated with increased injury mortality amongst infants and 20-24 year olds, and increased non-communicable disease mortality amongst 20-24 year old females. The strength of these associations tended to increase during adolescence. Increasing GDP was negatively associated with all-cause, communicable and non-communicable disease mortality in males and females across all age groups. GDP was also associated with decreased injury mortality in all age groups except 15-19 year old females, and 15-24 year old males. GDP became a weaker predictor of mortality during adolescence.Conclusion: Policies to reduce income inequality, rather than prioritising economic growth at all costs, may be needed to improve adolescent mortality in low and middle-income countries, a key development priority. [ABSTRACT FROM AUTHOR]

Correction to: I Nature Communications i https://doi.org/10.1038/s41467-023-39248-0, published online 19 June 2023 The original version of this Article contained an error in Fig. The original article can be found online at https://doi.org/10.1038/s41467-023-39248-0. [Extracted from the article]

The main goal of this paper is to introduce a novel meshless kernel Galerkin method for numerically solving partial differential equations on the sphere. Specifically, we will use this method to treat the partial differential equation for stationary heat conduction on S2, in an inhomogeneous, anisotropic medium. The Galerkin method used to do this employs spatially well-localized, "small footprint", robust bases for the associated kernel space. The stiffness matrices arising in the problem have entries decaying exponentially fast away from the diagonal. Discretization is achieved by first zeroing out small entries, resulting in a sparse matrix, and then replacing the remaining entries by ones computed via a very efficient kernel quadrature formula for the sphere. Error estimates for the approximate Galerkin solution are also obtained. [ABSTRACT FROM AUTHOR]

Background: The development and use of core outcome sets (COSs) in trials may improve data synthesis and reduce outcome reporting bias. The selection of outcomes in COSs is informed by views of key stakeholders, yet little is known about the role and influence of different stakeholders' views during COS development. We report an exploratory case study examining how stakeholder selection and incorporation of stakeholders' views may influence the selection of outcomes for a COS in reconstructive breast surgery (RBS). We also make recommendations for future considerations. Methods: Key stakeholder groups and subgroups were identified from the literature and expert opinion by the COS management group. They included health care professionals, subdivided by profession (breast and plastic surgeons, specialist nurses and psychologists) and patients, subdivided according to type of surgery received, timing of reconstruction, time since surgery and patient age. All participated in a survey in which they were asked to prioritise outcomes. Outcomes were prioritised using a 9-point scale from 1 (not important) to 9 (extremely important). The proportion of (1) all participants, ignoring stakeholder group (single heterogeneous panel analysis), (2) 'professional' and 'patient' groups separately (two heterogeneous panels), ignoring prespecified subgroups and (3) each participant subgroup separately (multiple homogeneous panel analysis) rating each item 'extremely important' was summarised and compared to explore how selection and integration of stakeholder views may influence outcome prioritisation. Results: There were many overlaps between items rated as most important by all groups. Specific stakeholders, however, prioritised specific concerns and a broader range of outcomes were prioritised when the subgroups were considered separately. For example, two additional outcomes were prioritised when patient and professional groups were considered separately and eight additional outcomes were identified when the views of the individual subgroups were explored. In general, patient subgroups preferentially valued additional clinical outcomes, including unplanned surgery, whereas professional subgroups prioritised additional psychosocial issues including body image. Conclusion: Stakeholder groups value different outcomes. Selection of groups, therefore, is important. Our recommendations for robust and transparent stakeholder selection and integration of stakeholder views may aid future COS developers in the design and conduct of their studies and improve the validity and value of future COS. [ABSTRACT FROM AUTHOR]

Monocytes are critical to the pathogenesis of inflammatory bowel disease (IBD) as they infiltrate the mucosa and release cytokines that drive the inflammatory response. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with anti-inflammatory actions, has been proposed as a potential new therapy for IBD. However, its effects on monocyte function are not yet known. Primary monocytes from healthy volunteers or cultured U937 monocytes were treated with either the proinflammatory cytokine, TNFα (5 ng/ml) or the bacterial endotoxin, lipopolysaccharide (LPS; 1 μg/ml) for 24 h, in the absence or presence of UDCA (25–100 μM). IL-8 release into the supernatant was measured by ELISA. mRNA levels were quantified by qPCR and changes in cell signaling proteins were determined by Western blotting. Toxicity was assessed by measuring lactate dehydrogenase (LDH) release. UDCA treatment significantly attenuated TNFα-, but not LPS-driven, release of IL-8 from both primary and cultured monocytes. UDCA inhibition of TNFα-driven responses was associated with reduced IL-8 mRNA expression. Both TNFα and LPS stimulated NFκB activation in monocytes, while IL-8 release in response to both cytokines was attenuated by an NFκB inhibitor, BMS-345541. Interestingly, UDCA inhibited TNFα-, but not LPS-stimulated, NFκB activation. Finally, TNFα, but not LPS, induced phosphorylation of TNF receptor associated factor (TRAF2), while UDCA cotreatment attenuated this response. We conclude that UDCA specifically inhibits TNFα-induced IL-8 release from monocytes by inhibiting TRAF2 activation. Since such actions would serve to dampen mucosal immune responses in vivo, our data support the therapeutic potential of UDCA for IBD. [ABSTRACT FROM AUTHOR]

Aim: Education is one of the strongest social determinants of health, yet previous literature has focused on primary education. We examined whether there are additional benefits to completing upper secondary compared to lower secondary education in a middle-income country. Methods: We performed a longitudinal analysis of the Cape Area Panel Study, a survey of adolescents living in South Africa. We undertook causal modeling using structural marginal models to examine the association between level of education and various health outcomes, using inverse probability weighting to control for sex, age, ethnicity, home language, income, whether employed in past year, region of birth, maternal educational status, marital status, whether currently pregnant and cognitive ability. Educational attainment was defined as primary (grades 1–7), lower secondary (grades 8–9) or upper secondary (grades 10–12). Results: Of 3,432 participants, 165 (4.8%) had completed primary education, 646 (18.8%) lower secondary and 2,621 (76.3%) upper secondary. Compared to those completing lower secondary, males completing upper secondary education were less likely to have a health problem (OR 0.49; 95%CI 0.27–0.88; p = 0.02); describe their health as poor (0.52; 0.29–0.95; p = 0.03) or report that health interferes with daily life (0.54; 0.29–0.99; p = 0.047). Females were less likely to have been pregnant (0.45; 0.33–0.61; p<0.001) or pregnant under 18 (0.32; 0.22–0.46; p<0.001); and having had sex under 16 was also less likely (males 0.63; 0.44–0.91; p = 0.01; females 0.39; 0.26–0.58; p<0.001). Cigarette smoking was less likely (males 0.52; 0.38–0.70; p = <0.001; females 0.56; 0.41–0.76; p<0.001), as was taking illicit drugs in males (0.6; 0.38–0.96; p = 0.03). No associations were found between education and alcohol use, psychological distress, obesity, increased waist circumference or hypertension. Conclusion: Completing upper secondary education was associated with improved health outcomes compared with lower secondary education. Expanding upper secondary education offers middle-income countries an effective way of improving adolescent health. [ABSTRACT FROM AUTHOR]