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HLA-B27 and spondyloarthritis: at the crossroads of innate and adaptive immunity.
HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8+ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4+ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs.
The Skeletal Ciliopathies
Within the broad and growing spectrum of human ciliopathies is a range of linked and overlapping disorders that present with skeletal features. These have been coined the skeletal ciliopathies. The syndromes have, to this point, been largely attributed to alterations in cellular Hedgehog signalling during development. However, a huge surge in fundamental discovery and clinical research has unveiled a plethora of roles for cilia in biology. This implicates a range of molecular and cell processes in the pathogenesis of skeletal ciliopathies. Our understanding of bi-directional interactions between cilia and the extracellular matrix remains in its infancy. The identification of genes and causal mutations defines skeletal ciliopathies. Some of these genes, and the proteins they encode, are now being explored further, by means of cell, animal, and other model approaches, seeking to understand the molecular underpinnings of disease. However, given the relatively recent appreciation of links between cilia biology and human disease, there is much work to be done. This chapter will briefly introduce the primary cilium and its associated ‘ciliome’, before describing the ciliary-associated skeletal disorders and the genes with which they are associated. Where possible, it will expand upon our current mechanistic understanding.
Dietary fat quantity and composition influence hepatic lipid metabolism and metabolic disease risk in humans.
The excessive accumulation of intrahepatic triglyceride (IHTG) in the liver is a risk factor for metabolic diseases, including type 2 diabetes and cardiovascular disease. IHTG can excessively accumulate owing to imbalances in the delivery, synthesis, storage and disposal of fat to, in and from the liver. Although obesity is strongly associated with IHTG accumulation, emerging evidence suggests that the composition of dietary fat, in addition to its quantity, plays a role in mediating IHTG accumulation. Evidence from human cross-sectional and interventional studies indicates that diets enriched with saturated fat compared to other fat types and carbohydrates produce divergent effects on IHTG content. However, the mechanistic reasons for these observations remain unknown. Given the challenges of investigating such mechanisms in humans, cellular models are needed that can recapitulate human hepatocyte fatty acid metabolism. Here, we review what is known from human studies about how dietary fat, its quantity and composition contribute to IHTG accumulation. We also explore the effects of fatty acid composition on hepatocellular fat metabolism from data generated in cellular models to help explain the divergences observed in in vivo studies.
Functional analysis of fibroblasts and macrophages in head and neck paragangliomas
Background and aim: Head and neck paragangliomas (HNPGN) are tumours that carry significant morbidity The role of the stroma in the pathogenesis of HNPGN is not completely understood. This study explores the profile of fibroblasts and macrophages in HNPGN. Methods: Ten patients undergoing HNPGN surgery were recruited. CD68 and CD163 immunohistochemistry was performed for macrophage analysis; CD90 and podoplanin (PDPN) expression was examined to identify fibroblasts. RT-qPCR was performed on HNPGN tissue for macrophage- and fibroblast-associated molecules. Fibroblast cultures were established from HNPGN were analysed by RT-qPCR and flowcytometry. Confocal microscopy for MCT1 and MCT4 was performed in HNPGN. Results: CD68 and CD163 expressing macrophages were noted in HNPGN. CD90 and PDPN expressing cells were present in HNPGN. RT-qPCR analysis showed expression of phenotypic and functional macrophage- and fibroblast-associated molecules in HNPGN. RT-qPCR analysis of fibroblasts cultured from HNPGN confirmed the expression of several molecules including PDPN at comparable levels to healthy tissue fibroblasts. Expression of FAP, MCT-1, insulin receptor (CD220) and insulin growth factor receptor-2 (CD222) was noted on HNPGN derived fibroblasts on flowcytometry. MCT1 and MCT4 were expressed in HNPGN tumour cells and stromal macrophages in-situ. Conclusion: Fibroblasts and macrophages are present in the HNPGN tumour microenvironment, and several macrophage and fibroblast functional markers are expressed in HNPGN. Macrophages in HNPGN tissue express metabolic markers MCT1 and MCT4. Further analysis of the fibroblast and macrophage function in HNPGN will improve our understanding of their potential roles in tumour pathogenesis.
Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: an individual data-based meta-analysis of 24 prospective studies.
The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of 'placebo' controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13-25), 21 (IQR:15-28), and 32 (IQR:20-35), respectively. PTC defined as pVL <50 copies/mL at day 84 occurred in 4% (n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design.
Clinical predictors of treatment response to gabapentin in women with unexplained chronic pelvic pain.
INTRODUCTION: Chronic pelvic pain affects up to 24% of women worldwide and for up to 55% of these there is no associated pathology. Despite this there are no established treatments in this cohort. This is a secondary analysis of a randomised-controlled trial (GaPP2) to explore if there are measures which enable us to predict treatment outcome. METHODS: GaPP2 recruited women with chronic pelvic pain and no identified pathology and compared the response to gabapentin and placebo. This analysis used variables collected at baseline including validated questionnaires. Binary logistic regression was used to create models to explore whether baseline variables predicted treatment response. Treatment response was determined using 30% reduction in average pain intensity, 30% reduction in worst pain intensity and the Patient Global Impression of Change ('marked' or 'very marked' improvement) individually. We also explored whether baseline variables predicted the occurrence of side-effects (dizziness, visual disturbances and drowsiness). RESULTS: Using the Patient Global Impression of Change questionnaire, we found a significant binary logistic regression (p = 0.029, explaining 31% of the variance), with those with lower worst pain intensity (odds ratio (OR) of 0.393, 95% CI [0.217, 0.712]), lower bladder symptom score (OR = 0.788, CI [0.628, 0.989]), and higher mental component quality of life score (OR = 0.911, CI [0.840, 0.988]), more likely to have 'marked' or 'very marked' improvement when treated with gabapentin. We could not identify predictors of experiencing side-effects to gabapentin. However, we did find predictors of these in the placebo group (binary logistic regression (p = 0.009) and explained 33% of the variance). Worse mental health (OR = 1.247, CI [1.019, 1.525]) and lower baseline pain interference (OR = 0.687, CI [0.483, 0.978]) were associated with having side effects, whilst the use of hormones reduced the risk of experiencing side effects (OR = 0.239, CI [0.084, 0.676]). DISCUSSION: Researchers and clinicians are increasingly aware of the importance of personalised medicine and treatment decisions being driven by knowledge of what treatments work for whom. Our data suggests an important role of the Patient Global Impression of Change in clinical trials as it may better reflect balance between symptoms reduction and side-effects and therefore be more useful in clinician-patients joint decision making.
The benefit of national clinical guidelines for open lower limb fractures in reducing healthcare burden: A length of inpatient stay cost-analysis.
INTRODUCTION: Severe open lower limb fractures are complex and costly injuries. Studies reporting the costs associated with these injuries, the economic impact of complications, and the clinical benefit of adherence to national guidelines have been previously reported. However, the economic benefits of national guidelines and their relationship with length of inpatient stay have not been described. METHODS: An international retrospective cohort study, using length of stay as a proxy for in-hospital economic impact, comparing the duration of inpatient stay in countries with national guidelines and those without. RESULTS: In a cohort of 2641 patients from 16 countries, length of stay was 17 % lower in countries with national guidelines, equivalent to 2-3 fewer inpatient days per patient. This difference was primarily driven by a lower incidence of deep infection observed in countries with national clinical guidelines. CONCLUSION: The presence of national guidelines for the management of severe lower limb injuries is associated with both improved clinical outcomes and reduced length of stay and therefore healthcare burden. Whilst application and adoption of national guidelines is not without challenges, their implementation is associated with significant clinical and economic benefits.
Navigating Chronic Pouchitis: Pathogenesis, Diagnosis, and Management.
Chronic pouchitis affects 13% to 17% of patients with ileal pouch-anal anastomosis and ulcerative colitis, and 20% with a history of acute pouchitis. It is classified by antibiotic responsiveness into chronic antibiotic-dependent pouchitis and chronic antibioticrefractory pouchitis. Pathogenesis of chronic pouchitis can range from microbially mediated to more antibiotic-resistant and immune-mediated processes. A diagnostic index combining clinical, endoscopic, and histologic components is essential for clinical practice and research. In chronic antibiotic-dependent pouchitis, remission is managed with microbiota- or immune-targeted therapies. For chronic antibiotic-refractory pouchitis, immune-directed therapy is primary, with vedolizumab recommended for first-line treatment. Other advanced therapies rely on less definitive evidence, and efficacy may be reduced by precolectomy exposure. This article reviews the pathogenesis, diagnosis, and management of chronic pouchitis.
The Urgency Numeric Rating Scale: Psychometric Evaluation in Adults with Crohn's Disease.
INTRODUCTION: Bowel urgency has recently been recognized as a Crohn's disease (CD) symptom that substantially impacts patients' quality of life. The Urgency NRS is a single-item patient-reported outcome measure assessing bowel urgency severity in the past 24 h (0-10 scale). We aimed to evaluate the psychometric properties of the Urgency Numeric Rating Scale (NRS) in adults with moderately to severely active CD and to estimate thresholds for meaningful improvement and bowel urgency remission. METHODS: Psychometric analyses used pooled data from the Phase 3 VIVID-1 study of mirikizumab, where participants with CD completed the Urgency NRS and other assessments. The Patient Global Rating of Severity (PGRS) and Patient Global Impression of Change (PGIC) were used as primary anchors to estimate Urgency NRS thresholds representing meaningful improvement and remission. RESULTS: The Urgency NRS showed good test-retest reliability in participants who were stable based on PGRS and PGIC. It was moderately correlated with similar assessments and weakly correlated with endoscopic/laboratory assessments. It differentiated between participant subgroups varying in disease severity and quality of life based on PGRS and other assessments. It was sensitive to change, as Urgency NRS improvements during the trial differed between most PGRS change and PGIC categories. A 3-5-point reduction on the Urgency NRS represented meaningful improvement and a score of ≤ 2 represented remission. CONCLUSION: The Urgency NRS demonstrated strong psychometric properties in the VIVID-1 population of moderately to severely active CD. Analyses also suggested meaningful improvement and remission thresholds. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03926130. Registered 23 April 2019, https://clinicaltrials.gov/study/NCT03926130 .
Gaps in acute upper GI bleed (AUGIB) endoscopy training: a UK trainees and trainers’ survey
IntroductionTrainees report inadequate exposure and training barriers in acute upper gastrointestinal bleed (AUGIB) endoscopic management. This UK-wide survey evaluated the experiences of trainees and trainers in AUGIB endoscopy training.MethodsA questionnaire was distributed to UK upper GI endoscopy trainees and trainers in 2022–2023.ResultsWe received responses from 137 trainees (23%) and 115 trainers (76%). Trainees reported higher exposure to diagnostic oesophagogastroduodenoscopies (OGDs) than AUGIB endoscopy (median 300, IQR 203–441 vs 15, IQR 2.5–35.5 lifetime procedures), with variations among grades and regions. Among trainees, 55% were specialist trainee (ST)3–5 and 28% ST6–7; 73% had Joint Advisory Group (JAG) certification for OGDs, and 32% attended a JAG-approved haemostasis course. For ST6–7 trainees, the highest lifetime procedure counts were for band ligation (median 20, IQR 8.5–39) and injection therapy (median 10, IQR 6.5–29.5); the lowest counts were for glue, over-the-scope clip and Danis stent (median 0). ≤41% of ST6–7 trainees felt confident in independent haemostatic procedures. Most trainees (68%) and trainers (64%) reported difficulties in AUGIB endoscopy training. Key barriers included lack of structured training (94% trainees), not being part of the AUGIB on-call rota (78% trainees and 72% trainers) and intensive acute-take commitments (75% trainees and 85% trainers). Suggested improvements included mandatory AUGIB on-call rota participation (89% trainees and 85% trainers), access to JAG-approved haemostasis courses (85% trainees and 84% trainers), simulation-based training (83% trainees and 72% trainers) and reduced acute-take commitments (80% trainees and trainers).ConclusionThis survey highlights limited exposure to haemostasis procedures and low perceived competence among UK trainees. Addressing these challenges provides an opportunity for targeted improvements, ensuring a more comprehensive training experience.
Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.
Assessing and Managing Primary Hyperparathyroidism and Fracture Risk in England: A Survey of Medical Professionals.
PURPOSE: To describe diagnostic approaches and management strategies for patients with primary hyperparathyroidism (PHPT) and recent fracture in England. METHODS: We developed a survey based on a patient at high fracture risk and a new diagnosis of probable PHPT. The survey was circulated among 50 secondary care professionals identified by the Society for Endocrinology Calcium and Bone special interest group. Descriptive statistics, combinatorial, and thematic analyses were employed. RESULTS: In the patient with hyperparathyroidism and a recent fracture, 54% of respondents favoured a 24-hour urinary calcium: creatinine clearance ratio, with 85% opting to do so after correcting vitamin D levels. Thirty-two percent (16/50) preferred the spot urinary calcium:creatinine clearance ratio, as a random test (56%, n = 9/16). Ninety-six percent of the respondents agreed they would include a fracture risk assessment in their management plan. Eighty-five percent of the respondents selected dual-energy X-ray absorptiometry scans of the lumbar spine, total hip, and femoral neck as the most popular choice. Before initiating antiosteoporotic medications (AOMs), 94% of the respondents preferred correcting vitamin D levels with diverse regimens. IV zoledronate acid was the preferred AOM, and 58% (n = 29/50) supported cinacalcet usage if the patient was ineligible for parathyroid surgery, while 26% (n = 13/50) opposed cinacalcet use entirely. No significant correlation was found between status as an endocrinology consultant or working in a tertiary care hospital and these management preferences. MAIN CONCLUSION: This study of National Health Service medical staff identified highly-varied clinical practices in managing PHPT in the setting of high fracture risk, highlighting the need for pragmatic guidelines and wider education.
Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models.
Loss of IFNγ-sensitivity by tumours is thought to be a mechanism enabling evasion, but recent studies suggest that IFNγ-resistant tumours can be sensitised for immunotherapy, yet the underlying mechanism remains unclear. Here, we show that IFNγ receptor-deficient B16-F10 mouse melanoma tumours are controlled as efficiently as WT tumours despite their lower MHC class I expression. Mechanistically, IFNγ receptor deletion in B16-F10 tumours increases IFNγ availability, triggering a remodelling of the immune landscape characterised by inflammatory monocyte infiltration and the generation of 'mono-macs'. This altered myeloid compartment synergises with an increase in antigen-specific CD8+ T cells to promote anti-tumour immunity against IFNγ receptor-deficient tumours, with such an immune crosstalk observed around blood vessels. Importantly, analysis of transcriptomic datasets suggests that similar immune remodelling occurs in human tumours carrying mutations in the IFNγ pathway. Our work thus serves mechanistic insight for the crosstalk between tumour IFNγ resistance and anti-tumour immunity, and implicates this regulation for future cancer therapy.
Novel Method for Routine Ultrasound-Guided Serum Collection for Biomarker Analysis Around the Knee Joint
Background Biomarkers are essential tools in modern medicine, allowing stratification and monitoring of clinical care and treatment response. While systemic blood biomarkers, typically collected from the antecubital vein (AV), are widely used, their sensitivity for joint-specific pathologies such as osteoarthritis (OA) may be limited due to systemic dilution. At present, no serum biomarker reliably reflects the microenvironment of an affected joint in clinical practice. Although synovial fluid (SF) assessment can provide insights into localised pathology and are clinically used for diagnosis in crystal arthropathies and joint infections, their collection is invasive, painful, and carries risks, including infection, making repeated sampling impractical, limiting utility for monitoring treatment responses. This study introduces a novel ultrasound-guided venous sampling technique targeting the saphenous vein (SV) proximal to the knee joint as a less invasive alternative to SF aspiration, hypothesising that it may better reflect the joint-specific microenvironment. Methods A standardised gel model was used to train medically qualified researchers in ultrasound-guided venepuncture of vescles around 2-15 mm in diameter. Subsequently, 32 participants consented to blood sampling from the SV above the knee, with a proximally applied tourniquet to dilate vein diameter for easier venepuncture collection. Results The technique achieved serum collection in over 80% of consented individuals with minimal adverse effects (including n=2 minor bruising and n=1 transient nerve irritation). Key procedural insights included optimal site selection, appropriate pressure application, and effective tourniquet use. Discussion This method demonstrates feasibility, acceptability, and the potential for more localised sample collection, advancing biomarker research. Further validation, including paired SF comparisons, is required to confirm diagnostic utility and develop therapeutic strategies for joint-specific conditions.
The Effect of Dark Chocolate Consumption on Arterial Function in Endurance Male Runners: Prospective Cohort Study.
Foods rich in polyphenols have beneficial effects on health. This study aimed to examine the impact of dark chocolate on endurance runners' arterial function. Forty-six male amateur runners, aged 25-55, participated. The initial assessments included clinical testing, arterial stiffness measurements, and a cardiopulmonary exercise test. The participants then consumed 50 g of dark chocolate (70% cocoa) daily for two weeks, maintaining their usual training routine. After this period, the baseline assessment was repeated. The results showed significant improvements. Pulse wave velocity decreased by 11.82% (p < 0.001), and augmentation index by 19.47% (p < 0.001). Systolic brachial blood pressure reduced by 2.12% (p < 0.05), diastolic by 2.79% (p < 0.05), and mean pressure by 2.41% (p < 0.05). Central arterial pressure also decreased, with systolic by 1.24% (p < 0.05), diastolic by 2.80% (p < 0.05), and mean pressure by 2.43% (p < 0.05). Resting heart rate increased by 4.57% (p < 0.05) and left ventricular ejection time decreased by 4.89% (p < 0.05), particularly in athletes over 40. Exercise time increased by 2.16% (p < 0.05), heart rate (max) by 1.15% (p < 0.05), VO2max by 2.31% (p < 0.05), and anaerobic threshold shifted by 6.91% (p < 0.001) in exercise time and 6.93% (p < 0.001) in VO2max. In conclusion, dark chocolate improves arterial function in endurance runners, enhancing vascular health.