Enhancing current guidance for psoriatic arthritis and its comorbidities: recommendations from an expert consensus panel.

OBJECTIVES: Existing guidelines for psoriatic arthritis (PsA) cover many aspects of management. Some gaps remain relating to routine practice application. An expert group aimed to enhance current guidance and develop recommendations for clinical practice that are complementary to existing guidelines. METHODS: A steering committee comprising experienced, research-active clinicians in rheumatology, dermatology and primary care agreed on themes and relevant questions. A targeted literature review of PubMed and Embase following a PICO framework was conducted. At a second meeting, recommendations were drafted and subsequently an extended faculty comprising rheumatologists, dermatologists, primary care clinicians, specialist nurses, allied health professionals, non-clinical academic participants and members of the Brit-PACT patient group, was recruited. Consensus was achieved via an online voting platform when 75% of respondents agreed in the range of 7-9 on a 9-point scale. RESULTS: The guidance comprised 34 statements covering four PsA themes. Diagnosis focused on strategies to identify PsA early and refer appropriately, assessment of diagnostic indicators, use of screening tools and use of imaging. Disease assessment centred on holistic consideration of disease activity, physical functioning and impact from a patient perspective, and on how to implement shared decision-making. For comorbidities, recommendations included specific guidance for high-impact conditions such as depression and obesity. Management statements (which excluded extant guidance on pharmacological therapies) covered multidisciplinary team working, implementation of lifestyle modifications and treat-to-target strategies. Minimising corticosteroid use was recommended where feasible. CONCLUSION: The consensus group have made evidence-based best practice recommendations for the management of PsA to enhance the existing guidelines.

Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope.

V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage.IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage.

Switching anti-CGRP monoclonal antibodies in chronic migraine: real-world observations of erenumab, fremanezumab and galcanezumab.

OBJECTIVES: The anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAb) are effective in migraine; however, few studies have examined the benefit of switching from one anti-CGRP-mAb to another. In order to better inform clinical practice in this situation, we present our real-world findings of switching anti-CGRP-mAb in chronic migraine. METHODS: Individuals with chronic migraine that switched anti-CGRP-mAb treatment (erenumab, fremanezumab or galcanezumab) due to ineffectiveness or adverse effects were retrospectively identified. Headache diary data before and up to 6 months after anti-CGRP-mAb switch were analysed. Main outcome measures were monthly red days (days with headaches limiting activity or requiring triptans), headache days (days with any kind of headache), triptan use, other analgesic use and headache disability (Headache Impact Test-6 (HIT-6) score) at 3 months. RESULTS: The analysis included 66 instances of switching among 54 individuals. There were non-significant reductions of -1.2 (-2.7, 0.3) red days from baseline at 3 months, with 10 individuals (15%) showing ≥50% improvement and 22 (33%) experiencing a ≥30% improvement. Improvements in headache days, triptan days, other painkiller use and HIT-6 score were non-significant. When individuals that switched due to side effects were excluded from the analysis, significant reductions in headache (Friedman p=0.044) and a trend for improvement in red days (Friedman p=0.083) were observed. With regard to side effects, on 12 occasions these improved or resolved on switching to a different anti-CGRP-mAb, while new symptoms were reported on eight occasions following a switch. CONCLUSION: We recorded modest improvements in headache outcomes, although significant results were only observed in those that switched anti-CGRP-mAb due to ineffectiveness. Switching may therefore be a viable option for these individuals.

The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope.

This guideline will provide up-to-date, evidence-based recommendations on the safe use of non-biologic DMARDs, also called conventional synthetic DMARDs (csDMARD), across the full spectrum of autoimmune rheumatic diseases. The guideline will update the guideline published in 2017 and will be expanded to include people of all ages. Updated information on the monitoring of DMARDs and vaccinations will be included. The guideline will be developed using the methods and processes described in the British Society for Rheumatology's 'Creating clinical guidelines: our protocol', updated 2023.

Expectations and experiences of screen time, social interaction, and solitude.

The current research examined how people forecast and experience screen time, social interaction, and solitude. When participants could freely use their smartphone, they forecasted (Study 1) and experienced (Study 2) better mood for face-to-face conversation, but worse mood for sitting alone. When participants were instructed to engage in specific screen time activities, they forecasted (Study 3) and experienced (Study 4) the best mood after watching television; followed by conversation, texting, and browsing social media (no difference); then sitting alone. Although participants in Studies 1 and 2 ranked conversation as their most preferred activity, participants in Studies 3 and 4 ranked it below television and texting, even though conversation improved mood compared to baseline (Study 4). These findings suggest that people may use their smartphones because they enable them to escape the unpleasant experience of being alone, or because they do not recognize or prioritize the mood benefits of social interaction.

Social determinants of ethnic disparities in SARS-CoV-2 infection: UK Biobank SARS-CoV-2 Serology Study.

BACKGROUND: The social determinants of ethnic disparities in risk of SARS-CoV-2 infection during the first wave of the pandemic in the UK remain unclear. METHODS: In May 2020, a total of 20 195 adults were recruited from the general population into the UK Biobank SARS-CoV-2 Serology Study. Between mid-May and mid-November 2020, participants provided monthly blood samples. At the end of the study, participants completed a questionnaire on social factors during different periods of the pandemic. Logistic regression yielded ORs for the association between ethnicity and SARS-CoV-2 immunoglobulin G antibodies (indicating prior infection) using blood samples collected in July 2020, immediately after the first wave. RESULTS: After exclusions, 14 571 participants (mean age 56; 58% women) returned a blood sample in July, of whom 997 (7%) had SARS-CoV-2 antibodies. Seropositivity was strongly related to ethnicity: compared with those of White ethnicity, ORs (adjusted for age and sex) for Black, South Asian, Chinese, Mixed and Other ethnic groups were 2.66 (95% CI 1.94-3.60), 1.66 (1.15-2.34), 0.99 (0.42-1.99), 1.42 (1.03-1.91) and 1.79 (1.27-2.47), respectively. Additional adjustment for social factors reduced the overall likelihood ratio statistics for ethnicity by two-thirds (67%; mostly from occupational factors and UK region of residence); more precise measurement of social factors may have further reduced the association. CONCLUSIONS: This study identifies social factors that are likely to account for much of the ethnic disparities in SARS-CoV-2 infection during the first wave in the UK, and highlights the particular relevance of occupation and residential region in the pathway between ethnicity and SARS-CoV-2 infection.

Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort.

BACKGROUND: Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study. METHODS: We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R2 threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years. FINDINGS: Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R2 ≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence. INTERPRETATION: These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity. FUNDING: Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.

Persistence of SARS-CoV-2 antibodies over 18 months following infection: UK Biobank COVID-19 Serology Study.

BACKGROUND: Little is known about the persistence of antibodies after the first year following SARS-CoV-2 infection. We aimed to determine the proportion of individuals that maintain detectable levels of SARS-CoV-2 antibodies over an 18-month period following infection. METHODS: Population-based prospective study of 20 000 UK Biobank participants and their adult relatives recruited in May 2020. The proportion of SARS-CoV-2 cases testing positive for immunoglobulin G (IgG) antibodies against the spike protein (IgG-S), and the nucleocapsid protein (IgG-N), was calculated at varying intervals following infection. RESULTS: Overall, 20 195 participants were recruited. Their median age was 56 years (IQR 39-68), 56% were female and 88% were of white ethnicity. The proportion of SARS-CoV-2 cases with IgG-S antibodies following infection remained high (92%, 95% CI 90%-93%) at 6 months after infection. Levels of IgG-N antibodies following infection gradually decreased from 92% (95% CI 88%-95%) at 3 months to 72% (95% CI 70%-75%) at 18 months. There was no strong evidence of heterogeneity in antibody persistence by age, sex, ethnicity or socioeconomic deprivation. CONCLUSION: This study adds to the limited evidence on the long-term persistence of antibodies following SARS-CoV-2 infection, with likely implications for waning immunity following infection and the use of IgG-N in population surveys.

HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC.

The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual's HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections.

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection.

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.

Childhood correlates of adult positive mental well-being in three British longitudinal studies.

BACKGROUND: Previous evidence has shown how experiences within childhood, such as parenting and socioeconomic conditions, are associated later on in life with adult mental well-being. However, these studies tend to focus on childhood experiences in isolation, and fewer studies have investigated how multiple aspects of the childhood environment, including both socioeconomic and psychosocial aspects, are associated with adult positive mental well-being. Using data from three British birth cohort studies, we investigated how prospective measures of the childhood environment up to the age of 16 years were associated with midlife adult mental well-being and whether similar associations were replicated across different generations. METHODS: Childhood environment comprised socioeconomic circumstances, psychosocial factors (child-rearing and parenting, family instability) and parental health. The Warwick-Edinburgh Mental Wellbeing Scale, a validated instrument measuring both hedonic and eudaemonic aspects of well-being, was administered in mid-life. We modelled associations between childhood environment domains and well-being. RESULTS: Despite changes in social context in all three studies, poorer quality parent-child relationships and poor parental mental health were strongly and independently associated with poorer adult mental well-being. Socioeconomic circumstances were also associated with adult mental well-being, but the association was weaker than for the measures of parenting or parental mental health. CONCLUSION: These findings confirm that parenting and parental mental health, as well as socioeconomic circumstances, are important for adult mental well-being. Interventions in early childhood aimed at reducing socioeconomic adversity and offering support to parents might be warranted, to enhance adult mental well-being later on in the life course.

Biomarker Testing for People With Advanced Lung Cancer in England.

INTRODUCTION: Optimal management of people with advanced NSCLC depends on accurate identification of predictive markers. Yet, real-world data in this setting are limited. We describe the impact, timeliness, and outcomes of molecular testing for patients with advanced NSCLC and good performance status in England. METHODS: In collaboration with Public Health England, patients with stages IIIB to IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 0 to 2, in England, between June 2017 and December 2017, were identified. All English hospitals were invited to record information. RESULTS: A total of 60 of 142 invited hospitals in England participated in this study and submitted data on 1157 patients. During the study period, 83% of patients with advanced adenocarcinoma underwent molecular testing for three recommended predictive biomarkers (EGFR, ALK, and programmed death-ligand 1). A total of 80% of patients with nonsquamous carcinomas on whom biomarker testing was performed had adequate tissue for analysis on initial sampling. First-line treatment with a tyrosine kinase inhibitor was received by 71% of patients with adenocarcinoma and a sensitizing EGFR mutation and by 59% of those with an ALK translocation. Of patients with no driver mutation and a programmed death-ligand 1 expression of greater than or equal to 50%, 47% received immunotherapy. CONCLUSIONS: We present a comprehensive data set for molecular testing in England. Although molecular testing is well established in England, timeliness and uptake of targeted therapies should be improved.

Scars of childhood socioeconomic stress: A systematic review.

Childhood socioeconomic position (SEP) is associated with the development of adult psychological outcomes, with DNA methylation (DNAm) as a mechanism to potentially explain these changes. We present the first systematic review synthesising the literature investigating childhood SEP and DNAm. Thirty-two publications were included. Seventeen studies focused on candidate genes, typically focusing on genes implicated with the stress response and/or development of psychiatric conditions. These studies typically investigated different regions of the genes, which revealed inconsistent results. Six studies calculated epigenetic age, with a small number revealing an elevated significant association with childhood SEP. Epigenome-wide studies revealed altered patterns of DNAm which varied between the nine studies. This research area is emerging and demonstrated great variance in findings with no clear patterns identified across studies. Multiple methodological shortcomings are identified, including at the phenotypic level where construct validity of childhood SEP is highly inconsistent, with studies using a wide range of measures. Larger cohorts will be required with international collaborations to strengthen this research area.

Experimental evidence indicating that mastreviruses probably did not co-diverge with their hosts.

BACKGROUND: Despite the demonstration that geminiviruses, like many other single stranded DNA viruses, are evolving at rates similar to those of RNA viruses, a recent study has suggested that grass-infecting species in the genus Mastrevirus may have co-diverged with their hosts over millions of years. This "co-divergence hypothesis" requires that long-term mastrevirus substitution rates be at least 100,000-fold lower than their basal mutation rates and 10,000-fold lower than their observable short-term substitution rates. The credibility of this hypothesis, therefore, hinges on the testable claim that negative selection during mastrevirus evolution is so potent that it effectively purges 99.999% of all mutations that occur. RESULTS: We have conducted long-term evolution experiments lasting between 6 and 32 years, where we have determined substitution rates of between 2 and 3 x 10(-4) substitutions/site/year for the mastreviruses Maize streak virus (MSV) and Sugarcane streak Réunion virus (SSRV). We further show that mutation biases are similar for different geminivirus genera, suggesting that mutational processes that drive high basal mutation rates are conserved across the family. Rather than displaying signs of extremely severe negative selection as implied by the co-divergence hypothesis, our evolution experiments indicate that MSV and SSRV are predominantly evolving under neutral genetic drift. CONCLUSION: The absence of strong negative selection signals within our evolution experiments and the uniformly high geminivirus substitution rates that we and others have reported suggest that mastreviruses cannot have co-diverged with their hosts.

Marriage and physical capability at mid to later life in England and the USA.

BACKGROUND: Married people have lower rates of mortality and report better physical and mental health at older ages, compared to their unmarried counterparts. However, there is limited evidence on the association between marriage and physical capability, the ability to carry out the tasks of daily living, which is predictive of future mortality and social care use. We investigate the association between marital status and physical capability at mid to later life in England and the United States. METHODS: We examine the association between marriage and physical capability at mid to later life in England and the USA using two performance-based measures of physical capability: grip strength and walking speed. Multiple linear regression was carried out on Wave 4 (2008) of the English Longitudinal Study of Ageing (ELSA) and Waves 8 and 9 (2006 and 2008) of the US Health and Retirement Study (HRS). RESULTS: In age adjusted models married men and women had better physical capability than their unmarried counterparts. Much of the marriage advantage was explained by the greater wealth of married people. However, remarried men were found to have stronger grip strength and widowed and never married men had a slower walking speed than men in their first marriage, which was not explained by wealth, demographic and socioeconomic characteristics, health behaviours, chronic disease or depressive symptoms. There were no differences in the association between England and the USA. CONCLUSIONS: Marriage may be an important factor in maintaining physical capability in both England and the USA, particularly because of the greater wealth which married people have accrued by the time they reach older ages. The grip strength advantage for remarried men may be due to unobserved selective factors into remarriage.

Structural Rearrangements Maintain the Glycan Shield of an HIV-1 Envelope Trimer After the Loss of a Glycan.

The HIV-1 envelope (Env) glycoprotein is the primary target of the humoral immune response and a critical vaccine candidate. However, Env is densely glycosylated and thereby substantially protected from neutralisation. Importantly, glycan N301 shields V3 loop and CD4 binding site epitopes from neutralising antibodies. Here, we use molecular dynamics techniques to evaluate the structural rearrangements that maintain the protective qualities of the glycan shield after the loss of glycan N301. We examined a naturally occurring subtype C isolate and its N301A mutant; the mutant not only remained protected against neutralising antibodies targeting underlying epitopes, but also exhibited an increased resistance to the VRC01 class of broadly neutralising antibodies. Analysis of this mutant revealed several glycans that were responsible, independently or through synergy, for the neutralisation resistance of the mutant. These data provide detailed insight into the glycan shield's ability to compensate for the loss of a glycan, as well as the cascade of glycan movements on a protomer, starting at the point mutation, that affects the integrity of an antibody epitope located at the edge of the diminishing effect. These results present key, previously overlooked, considerations for HIV-1 Env glycan research and related vaccine studies.