Temporal trends in mode, site and stage of presentation with the introduction of colorectal cancer screening: a decade of experience from the West of Scotland

background:  Population colorectal cancer screening programmes have been introduced to reduce cancer-specific mortality through the detection of early-stage disease. The present study aimed to examine the impact of screening introduction in the West of Scotland. methods:  Data on all patients with a diagnosis of colorectal cancer between January 2003 and December 2012 were extracted from a prospectively maintained regional audit database. Changes in mode, site and stage of presentation before, during and after screening introduction were examined. results:  In a population of 2.4 million, over a 10-year period, 14 487 incident cases of colorectal cancer were noted. Of these, 7827 (54%) were males and 7727 (53%) were socioeconomically deprived. In the postscreening era, 18% were diagnosed via the screening programme. There was a reduction in both emergency presentation (20% prescreening vs 13% postscreening, P0.001) and the proportion of rectal cancers (34% prescreening vs 31% pos-screening, P0.001) over the timeframe. Within non-metastatic disease, an increase in the proportion of stage I tumours at diagnosis was noted (17% prescreening vs 28% postscreening, P0.001). conclusions:  Within non-metastatic disease, a shift towards earlier stage at diagnosis has accompanied the introduction of a national screening programme. Such a change should lead to improved outcomes in patients with colorectal cancer

Precision medicine in psoriatic arthritis: how should we select targeted therapies?

Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis associated with psoriasis. Patients manifest variable presentations with potential involvement of peripheral joints, spine, tendons, skin, and nails. There has been a rapid expansion in targeted treatment options for patients with PsA, but typically less than half of those who receive therapy achieve optimal treatment targets. Many patients respond to second-line or third-line biological therapies, but little evidence exists to guide the choice of therapeutics for each individual. At present, choice of therapy is driven by active clinical disease domains, clinician familiarity with existing treatments, and cost. Here, we review recent data that highlight the potential for personalised, or precision, medicine in PsA and other forms of inflammatory arthritis, noting that this research is still at a preliminary stage. In the future, a combination of detailed immunophenotyping and sophisticated statistical analyses should help to facilitate a personalised medicine approach in PsA, following examples from other clinical areas, such as oncology. This change in approach to the treatment of PsA has the potential to maximise outcomes for patients and to provide optimal therapies without delay

Differences in male and female mice in a model of early osteoarthritis

Osteoarthritis is a prevalent musculoskeletal disease characterised by joint degeneration and pain. Over the age of 50, women are twice as likely to develop osteoarthritis than men. Given the importance of biological sex in osteoarthritis, we compared early osteoarthritis in male and female mice. We induced osteoarthritis via surgical destabilisation of the medial meniscus and cartilage scratch (DCS) on 10-week-old male and female mice (n=8). Two weeks after induction we characterised joint parameters via microCT and histology, and pain behaviours by dynamic weight bearing (DWB). We ovariectomised (OVX) 8-week-old females (n=10) and induced osteoarthritis at 11 weeks old. We assessed for pain behaviours via DWB and von Frey testing. Contralateral and ipsilateral dorsal root ganglion (DRG) of male, female sham OVX and female OVX were dissected and processed for gene expression RNAseq analysis. Male mice showed 31.2 ± 4.5% increase in subchondral bone osteoclerosis while female mice showed a minimal 4.42 ± 6.23 % change in subchondral bone (P < 0.001). There were no significant differences in cartilage damage, synovitis or osteophytogenesis. Males loaded their osteoarthritic leg less than the contralateral (paired t-test P < 0.01), which indicates discomfort. None of the female mice or OVX female mice showed this change in loading. Female OVX mice showed a decrease in mechanical withdrawal threshold in the osteoarthritic leg (0.3 ± 0.12) when compared to the contralateral leg (0.5 ± 0.24, P < 0.05). There were no significant changes in DRG gene expression when comparing osteoarthritic to contralateral side in any of the groups. Female DRG show downregulation of genes involved neuron projection guidance and calcium ion transmembrane transport when compared to males. Female OVX mice showed an upregulation of lymphocyte development pathways when compared to female sham OVX DRG. The main differences observed in early osteoarthritis between male and female mice resided in the bone and display of pain. Female mice in general have a slower bone modelling rate, which here translates into lower subchondral osteosclerosis. Interestingly, female mice did not display differential pain behaviours compared to male mice, which could be related to the gene expression changes observed in the DRG

Sialylation of campylobacter jejuni lipo-oligosaccharides: impact on phagocytosis and cytokine production in mice

Background: Guillain-Barré syndrome (GBS) is a post-infectious polyradiculoneuropathy, frequently associated with antecedent Campylobacter jejuni (C. jejuni) infection. The presence of sialic acid on C. jejuni lipo-oligosaccharide (LOS) is considered a risk factor for development of GBS as it crucially determines the structural homology between LOS and gangliosides, explaining the induction of cross-reactive neurotoxic antibodies. Sialylated C. jejuni are recognised by TLR4 and sialoadhesin; however, the functional implications of these interactions in vivo are unknown. Methodology/Principal Findings: In this study we investigated the effects of bacterial sialylation on phagocytosis and cytokine secretion by mouse myeloid cells in vitro and in vivo. Using fluorescently labelled GM1a/GD1a ganglioside-mimicking C. jejuni strains and corresponding (Cst-II-mutant) control strains lacking sialic acid, we show that sialylated C. jejuni was more efficiently phagocytosed in vitro by BM-MΦ, but not by BM-DC. In addition, LOS sialylation increased the production of IL-10, IL-6 and IFN-β by both BM-MΦ and BM-DC. Subsequent in vivo experiments revealed that sialylation augmented the deposition of fluorescent bacteria in splenic DC, but not macrophages. In addition, sialylation significantly amplified the production of type I interferons, which was independent of pDC. Conclusions/Significance: These results identify novel immune stimulatory effects of C. jejuni sialylation, which may be important in inducing cross-reactive humoral responses that cause GBS

How Experiences Become Data: The Process of Eliciting Adverse Event, Medical History and Concomitant Medication Reports in Antimalarial and Antiretroviral Interaction Trials.

Accurately characterizing a drug's safety profile is essential. Trial harm and tolerability assessments rely, in part, on participants' reports of medical histories, adverse events (AEs), and concomitant medications. Optimal methods for questioning participants are unclear, but different methods giving different results can undermine meta-analyses. This study compared methods for eliciting such data and explored reasons for dissimilar participant responses. Participants from open-label antimalarial and antiretroviral interaction trials in two distinct sites (South Africa, n = 18 [all HIV positive]; Tanzania, n = 80 [86% HIV positive]) were asked about ill health and treatment use by sequential use of (1) general enquiries without reference to particular conditions, body systems or treatments, (2) checklists of potential health issues and treatments, (3) in-depth interviews. Participants' experiences of illness and treatment and their reporting behaviour were explored qualitatively, as were trial clinicians' experiences with obtaining participant reports. Outcomes were the number and nature of data by questioning method, themes from qualitative analyses and a theoretical interpretation of participants' experiences. There was an overall cumulative increase in the number of reports from general enquiry through checklists to in-depth interview; in South Africa, an additional 12 medical histories, 21 AEs and 27 medications; in Tanzania an additional 260 medical histories, 1 AE and 11 medications. Checklists and interviews facilitated recognition of health issues and treatments, and consideration of what to report. Information was sometimes not reported because participants forgot, it was considered irrelevant or insignificant, or they feared reporting. Some medicine names were not known and answers to questions were considered inferior to blood tests for detecting ill health. South African inpatient volunteers exhibited a "trial citizenship", working to achieve researchers' goals, while Tanzanian outpatients sometimes deferred responsibility for identifying items to report to trial clinicians. Questioning methods and trial contexts influence the detection of adverse events, medical histories and concomitant medications. There should be further methodological work to investigate these influences and find appropriate questioning methods

The IĸB protein BCL3 controls osteogenesis and bone health.

OBJECTIVE: IĸB protein B-cell lymphoma 3-encoded protein (BCL3) is a regulator of the NF-κB family of transcription factors. NF-κB signalling fundamentally influences the fate of bone-forming osteoblasts and bone-resorbing osteoclasts, but the role of BCL3 in bone biology has not been investigated. The objective of this study was to evaluate BCL3 in skeletal development, maintenance and osteoarthritic pathology. METHODS: To assess the contribution of BCL3 to skeletal homeostasis, neonatal mice (n = 6-14) lacking BCL3 (Bcl3-/- ) and WT controls were characterised for bone phenotype and density. To reveal the contribution to bone phenotype by the osteoblast compartment in Bcl3-/- mice, transcriptomic analysis of early osteogenic differentiation and cellular function (n = 3-7) were assessed. Osteoclast differentiation and function in Bcl3-/- mice (n = 3-5) was assessed. Adult 20-week Bcl3-/- and WT mice bone phenotype, strength and turnover were assessed. A destabilisation of the medial meniscus (DMM) model of osteoarthritic ostephytogenesis was utilised to understand adult bone formation in Bcl3-/- mice (n = 11-13). RESULTS: Evaluation of Bcl3-/- mice revealed congenitally increased bone density, long bone dwarfism, increased bone biomechanical strength and altered bone turnover. Molecular and cellular characterisation of mesenchymal precursors showed that Bcl3-/- cells display an accelerated osteogenic transcriptional profile that leads to enhanced differentiation into osteoblasts with increased functional activity; which could be reversed with a mimetic peptide. In a model of osteoarthritis-induced osteophytogenesis, Bcl3-/- mice exhibit decreased pathological osteophyte formation (P < 0.05). CONCLUSION: Cumulatively, these findings demonstrate that BCL3 controls developmental mineralisation to enable appropriate bone formation, whilst in a pathological setting it contributes to skeletal pathology

The role of PAR2 in osteoblast differentiation versus function

Studies have revealed a bone-specific role for protease activated receptor 2 (PAR2) in the development of murine osteoarthritis. Notably, the absence of PAR2 leads to reduced osteosclerosis and osteophytogenesis. Although PAR2 can enhance osteoblast differentiation and callus formation during repair, there is no evidence for a role in the maintenance of the adult skeleton. The aim of this study was to investigate the role of PAR2 in mature osteoblasts. Osteoblast-PAR2 conditional knockout mice (PAR2ob/ob) were generated, and femur and tibia profiled at 5, 14 and 62-weeks. At 5-weeks, PAR2ob/ob showed significantly lower trabecular bone density (7.6%±0.9) in comparison to floxed controls (11.9%±2.4)(P=0.01). However, this difference resolved by 14-weeks. Aged mice (62-weeks) showed progressive bone loss, however, this was inconsistent across the floxed and PAR2ob/ob. Controls lost 51% of trabecular bone whilst PAR2ob/ob only lost 35% (P=0.004). To investigate additional cellular contributors to skeletal maintenance, chondrocyte-specific PAR2 knockouts were also generated and profiled. In this setting the opposite effect was observed; i.e., trabecular bone density was the same at 5-weeks and significantly decreased after 14-weeks. Providing a potential explanation for the lack of a bone phenotype in adult PAR2-global knockout mice. Finally, in vitro studies were undertaken to investigate mineralisation in a range of osteoblast states (i.e., bone marrow, neonatal calvarial osteoblasts and aged osteoblasts extracted from long bones). In the absence of PAR2, bone marrow cultures and neonatal calvarial pre-osteoblasts showed significantly lower alkaline phosphatase (WT 86.6±18, PAR2-/- 47.6±4, P=0.02) and mineralisation (WT 5.3±2.7, PAR2-/- 12.2±5, P=0.02), whilst mature differentiated aged osteoblasts had a 2 fold increase in mineral formation (P=0.03). In summary, these data highlight the difference between osteoblast differentiation and function, as well as the importance of age in the osteoblast. We hypothesise that whilst PAR2 enhances osteoblast differentiation, it inhibits the function of mature osteoblasts

Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis

\ua9 2025 The Author(s). Objectives: Inflammation triggered by endogenous stimuli that signal cellular stress or tissue injury must be tightly controlled to balance robust protection from intrinsic danger while avoiding catastrophic destruction of healthy tissues. Here, we assess the contribution of innate memory to this balance. Methods: Memory evoked by the extracellular matrix protein tenascin-C, a damage-associated, toll-like receptor 4 (TLR4) agonist, was compared to that induced by the pathogenic TLR4 agonist lipopolysaccharide (LPS) by transcriptomic and epigenetic profiling of monocytes from healthy individuals or people with rheumatoid arthritis (RA), and tissue macrophages from the RA synovium. Results: Tenascin-C reprograms monocyte response to subsequent threats, inducing concomitantly suppressed and enhanced responses to rechallenge. Comparative analysis of tenascin-C and LPS revealed common and distinct gene expression signatures, effects controlled transcriptionally and associated with stimulus-specific epigenetic mediators. Altered responses following rechallenge after priming with tenascin-C were not limited to subsequent TLR4 activation but were evident in response to various pathogenic and endogenous stimuli detected by different receptors. In healthy monocytes primed with tenascin-C, rechallenge with stimuli found at high levels in the joints of people with RA resulted in trained responses that were not induced by LPS, including genes associated with chronic inflammation, tissue destruction, altered metabolism, and poor treatment response in RA. The expression of a large subset of these genes was elevated in monocytes from people with RA in the absence of any stimulation and in RA synovial macrophage populations associated with disease flare. Moreover, higher levels of permissive complexes within key epigenetic nodes and increased bivalent modification creating poised loci within endogenously trained genes were observed in RA cells. Conclusions: These data highlight how innate reprogramming during ‘sterile’ inflammatory diseases contributes to chronicity, uncovering pathways unique to endogenous immune triggers that could provide disease-specific points of intervention without engendering global immune suppression