Increasing condom use in heterosexual men: development of a theory-based interactive digital intervention

Increasing condom use to prevent sexually transmitted infections is a key public health goal. Interventions are more likely to be effective if they are theory- and evidence-based. The Behaviour Change Wheel (BCW) provides a framework for intervention development. To provide an example of how the BCW was used to develop an intervention to increase condom use in heterosexual men (the MenSS website), the steps of the BCW intervention development process were followed, incorporating evidence from the research literature and views of experts and the target population. Capability (e.g. knowledge) and motivation (e.g. beliefs about pleasure) were identified as important targets of the intervention. We devised ways to address each intervention target, including selecting interactive features and behaviour change techniques. The BCW provides a useful framework for integrating sources of evidence to inform intervention content and deciding which influences on behaviour to target

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Confocal endomicroscopy for evaluation of pancreatic cystic lesions: a systematic review and international Delphi consensus report

Background and study aims The aim of thi systematic review and consensus report is to standardize the practice of endoscopic ultrasound (EUS-guided needle-based confocal laser endomicroscopy (nCLE) for pancreatic cystic lesion (PCL) evaluation. Methods We performed an international, systematic, evidence-based review of the applications, outcomes, procedural processes, indications, training, and credentialing of EUS-nCLE in management of PCLs. Based on available clinical evidence, preliminary nCLE consensus statements (nCLE-CS) were developed by an international panel of 15 experts in pancreatic diseases. These statements were then voted and edited by using a modified Delphi approach. An a priori threshold of 80 % agreement was used to establish consensus for each statement. Results Sixteen nCLE-CS were discussed. Thirteen (81 %) nCLE-CS reached consensus addressing indications (noncommunication PCL meeting criteria for EUS-FNA or with prior non-diagnostic EUS-FNA), diagnostic outcomes (improved accuracy for mucinous PCLs and serous cystadeno mas with substantial interobserver agreement of image patterns), low incidence of adverse events (fluoresceinassociated and pancreatitis), procedural processes (nCLE duration, manipulation of needle with probe), and training (physician knowledge and competence). Conclusion Based on a high level of agreement pertaining to expert consensus statements, this report standardizes the practice of EUS-nCLE. EUS-nCLE should be systematically considered when EUS-FNA is indicated for PCL evaluation

"Cognitive Penetrability" - Ch 3 of Seemings and Epistemic Justification

In this chapter I introduce the thesis that perceptual appearances are cognitively penetrable and analyse cases made against phenomenal conservatism hinging on this thesis. In particular, I focus on objections coming from the externalist reliabilist camp and the internalist inferentialist camp. I conclude that cognitive penetrability doesn’t yield lethal or substantive difficulties for phenomenal conservatism

Fatigue in primary Sjögren's syndrome (pSS) is associated with lower levels of proinflammatory cytokines: a validation study

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune rheumatic disease with symptoms including dryness, fatigue, and pain. The previous work by our group has suggested that certain proinflammatory cytokines are inversely related to patient-reported levels of fatigue. To date, these findings have not been validated. This study aims to validate this observation. Blood levels of seven cytokines were measured in 120 patients with pSS from the United Kingdom Primary Sjögren’s Syndrome Registry and 30 age-matched healthy non-fatigued controls. Patient-reported scores for fatigue were classified according to severity and compared to cytokine levels using analysis of variance. The differences between cytokines in cases and controls were evaluated using Wilcoxon test. A logistic regression model was used to determine the most important identifiers of fatigue. Five cytokines, interferon-γ-induced protein-10 (IP-10), tumour necrosis factor-α (TNFα), interferon-α (IFNα), interferon-γ (IFN-γ), and lymphotoxin-α (LT-α) were significantly higher in patients with pSS (n = 120) compared to non-fatigued controls (n = 30). Levels of two proinflammatory cytokines, TNF-α (p = 0.021) and LT-α (p = 0.043), were inversely related to patient-reported levels of fatigue. Cytokine levels, disease-specific and clinical parameters as well as pain, anxiety, and depression were used as predictors in our validation model. The model correctly identifies fatigue levels with 85% accuracy. Consistent with the original study, pain, depression, and proinflammatory cytokines appear to be the most powerful predictors of fatigue in pSS. TNF-α and LT-α have an inverse relationship with fatigue severity in pSS challenging the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions

Persistent Cell-Autonomous Circadian Oscillations in Fibroblasts Revealed by Six-Week Single-Cell Imaging of PER2::LUC Bioluminescence

Biological oscillators naturally exhibit stochastic fluctuations in period and amplitude due to the random nature of molecular reactions. Accurately measuring the precision of noisy oscillators and the heterogeneity in period and strength of rhythmicity across a population of cells requires single-cell recordings of sufficient length to fully represent the variability of oscillations. We found persistent, independent circadian oscillations of clock gene expression in 6-week-long bioluminescence recordings of 80 primary fibroblast cells dissociated from PER2::LUC mice and kept in vitro for 6 months. Due to the stochastic nature of rhythmicity, the proportion of cells appearing rhythmic increases with the length of interval examined, with 100% of cells found to be rhythmic when using 3-week windows. Mean period and amplitude are remarkably stable throughout the 6-week recordings, with precision improving over time. For individual cells, precision of period and amplitude are correlated with cell size and rhythm amplitude, but not with period, and period exhibits much less cycle-to-cycle variability (CV 7.3%) than does amplitude (CV 37%). The time series are long enough to distinguish stochastic fluctuations within each cell from differences among cells, and we conclude that the cells do exhibit significant heterogeneity in period and strength of rhythmicity, which we measure using a novel statistical metric. Furthermore, stochastic modeling suggests that these single-cell clocks operate near a Hopf bifurcation, such that intrinsic noise enhances the oscillations by minimizing period variability and sustaining amplitude

B-cell activity markers are associated with different disease activity domains in primary Sjögren's syndrome

OBJECTIVES: B-cell activating factor (BAFF), β-2 microglobulin (β2M) and serum free light chains (FLCs) are elevated in primary SS (pSS) and associated with disease activity. We aimed to investigate their association with the individual disease activity domains of the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) in a large well-characterized pSS cohort. METHODS: Sera from pSS patients enrolled in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) (n = 553) and healthy controls (n = 286) were analysed for FLC (κ and λ), BAFF and β2 M. Pearson correlation coefficients were calculated for patient clinical characteristics, including salivary flow, Schirmer’s test, EULAR Sjögren’s Syndrome Patient Reported Index and serum IgG levels. Poisson regression was performed to identify independent predictors of total ESSDAI and ClinESSDAI (validated ESSDAI minus the biological domain) scores and their domains. RESULTS: Levels of BAFF, β2M and FLCs were higher in pSS patients compared to controls. All three biomarkers associated significantly with the ESSDAI and the ClinESSDAI. BAFF associated with the peripheral nervous system domain of the ESSDAI, whereas β2M and FLCs associated with the cutaneous, biological and renal domains. Multivariate analysis showed BAFF, β2M and their interaction to be independent predictors of ESSDAI/ClinESSDAI. FLCs were also shown to associate with the ESSDAI/ClinESSDAI but not independent of serum IgG. CONCLUSION: All biomarkers were associated with total ESSDAI scores but with differing domain associations. These findings should encourage further investigation of these biomarkers in longitudinal studies and against other disease activity measures

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology