Daily Pain Severity but Not Vertebral Fractures Is Associated With Lower Physical Activity in Postmenopausal Women With Back Pain

Back pain lifetime incidence is 60%–70%, while 12%–20% of older women have vertebral fractures (VFs), often with back pain. We aimed to provide objective evidence, currently lacking, regarding whether back pain and VFs affect physical activity (PA). We recruited 69 women with recent back pain (age 74.5 ± 5.4 years). Low- (0.5  .11). VFs were not associated with PA (all p > .2). Higher daily pain levels but not VFs were associated with reduced low- and medium-impact PA, which could increase sarcopenia and falls risk in older women with back pain

Re-programming immunosurveillance in persistent non-infectious ocular inflammation

Ocular function depends on a high level of anatomical integrity. This is threatened by inflammation, which alters the local tissue over short and long time-scales. Uveitis due to autoimmune disease, especially when it involves the retina, leads to persistent changes in how the eye interacts with the immune system. The normal pattern of immune surveillance, which for immune privileged tissues is limited, is re-programmed. Many cell types, that are not usually present in the eye, become detectable. There are changes in the tissue homeostasis and integrity. In both human disease and mouse models, in the most extreme cases, immunopathological findings consistent with development of ectopic lymphoid-like structures and disrupted angiogenesis accompany severely impaired eye function. Understanding how the ocular environment is shaped by persistent inflammation is crucial to developing novel approaches to treatment

Re-programming immunosurveillance in persistent non-infectious ocular inflammation

Ocular function depends on a high level of anatomical integrity. This is threatened by inflammation, which alters the local tissue over short and long time-scales. Uveitis due to autoimmune disease, especially when it involves the retina, leads to persistent changes in how the eye interacts with the immune system. The normal pattern of immune surveillance, which for immune privileged tissues is limited, is re-programmed. Many cell types, that are not usually present in the eye, become detectable. There are changes in the tissue homeostasis and integrity. In both human disease and mouse models, in the most extreme cases, immunopathological findings consistent with development of ectopic lymphoid-like structures and disrupted angiogenesis accompany severely impaired eye function. Understanding how the ocular environment is shaped by persistent inflammation is crucial to developing novel approaches to treatment

A prospective cohort and extended comprehensive-cohort design provided insights about the generalizability of a pragmatic trial:the ProtecT prostate cancer trial

Objectives Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability. Study Design and Setting Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct. Results The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa. Conclusion The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice

Risk of SARS-CoV-2 reinfection during multiple Omicron variant waves in the UK general population

SARS-CoV-2 reinfections increased substantially after Omicron variants emerged. Large-scale community-based comparisons across multiple Omicron waves of reinfection characteristics, risk factors, and protection afforded by previous infection and vaccination, are limited. Here we studied ~45,000 reinfections from the UK’s national COVID-19 Infection Survey and quantified the risk of reinfection in multiple waves, including those driven by BA.1, BA.2, BA.4/5, and BQ.1/CH.1.1/XBB.1.5 variants. Reinfections were associated with lower viral load and lower percentages of self-reporting symptoms compared with first infections. Across multiple Omicron waves, estimated protection against reinfection was significantly higher in those previously infected with more recent than earlier variants, even at the same time from previous infection. Estimated protection against Omicron reinfections decreased over time from the most recent infection if this was the previous or penultimate variant (generally within the preceding year). Those 14–180 days after receiving their most recent vaccination had a lower risk of reinfection than those >180 days from their most recent vaccination. Reinfection risk was independently higher in those aged 30–45 years, and with either low or high viral load in their most recent previous infection. Overall, the risk of Omicron reinfection is high, but with lower severity than first infections; both viral evolution and waning immunity are independently associated with reinfection

A novel pathogenic RBP-3 peptide reveals epitope spreading in persistent experimental autoimmune uveoretinitis

Experimental autoimmune uveoretinitis (EAU) in the C57BL/6J mouse is a model of non-infectious posterior segment intraocular inflammation that parallels clinical features of the human disease. The purpose of this study was to analyse the immune response to the four murine subunits of retinol binding protein-3 (RBP-3) to identify pathogenic epitopes to investigate the presence of intramolecular epitope spreading during the persistent inflammation phase observed in this model of EAU. Recombinant murine subunits of the RBP-3 protein were purified and used to immunize C57BL/6J mice to induce EAU. An overlapping peptide library was used to screen RBP-3 subunit 3 for immunogenicity and pathogenicity. Disease phenotype and characterization of pathogenic subunits and peptides was undertaken by topical endoscopic fundal imaging, immunohistochemistry, proliferation assays and flow cytometry. RBP-3 subunits 1, 2 and 3 induced EAU in the C57BL/6J mice, with subunit 3 eliciting the most destructive clinical disease. Within subunit 3 we identified a novel uveitogenic epitope, 629–643. The disease induced by this peptide was comparable to that produced by the uveitogenic 1–20 peptide. Following immunization, peptide-specific responses by CD4(+) and CD8(+) T-cell subsets were detected, and cells from both populations were present in the retinal inflammatory infiltrate. Intramolecular epitope spreading between 629–643 and 1–20 was detected in mice with clinical signs of disease. The 629–643 RBP-3 peptide is a major uveitogenic peptide for the induction of EAU in C57BL/6J mice and the persistent clinical disease induced with one peptide leads to epitope spreading

Tissue-Resident Exhausted Effector Memory CD8+ T Cells Accumulate in the Retina during Chronic Experimental Autoimmune Uveoretinitis

Experimental autoimmune uveoretinitis is a model for noninfectious posterior segment intraocular inflammation in humans. Although this disease is CD4(+) T cell dependent, in the persistent phase of disease CD8(+) T cells accumulate. We show that these are effector memory CD8(+) T cells that differ from their splenic counterparts with respect to surface expression of CD69, CD103, and Ly6C. These retinal effector memory CD8(+) T cells have limited cytotoxic effector function, are impaired in their ability to proliferate in response to Ag-specific stimulation, and upregulate programmed death 1 receptor. Treatment with fingolimod (FTY720) during the late phase of disease revealed that retinal CD8(+) T cells were tissue resident. Despite signs of exhaustion, these cells were functional, as their depletion resulted in an expansion of retinal CD4(+) T cells and CD11b(+) macrophages. These results demonstrate that, during chronic autoimmune inflammation, exhausted CD8(+) T cells become established in the local tissue. They are phenotypically distinct from peripheral CD8(+) T cells and provide local signals within the tissue by expression of inhibitory receptors such as programmed death 1 that limit persistent inflammation

Daily pain severity but not vertebral fractures is associated with lower physical activity in postmenopausal women with back pain

Back pain lifetime incidence is 60-70%, whilst 12-20% of older women have vertebral fractures (VFs), often with back pain. We aimed to provide objective evidence, currently lacking, regarding whether back pain and VFs affect physical activity (PA).We recruited 69 women with recent back pain (age 74.5±5.4y). Low (0.50.11). VFs were not associated with PA (all p>0.2).Higher daily pain levels but not VFs were associated with reduced low and medium-impact PA, which could increase sarcopenia and falls risk in older women with back pain

Carbohydrate-responsive element-binding protein (ChREBP) is a negative regulator of ARNT/HIF-1beta gene expression in pancreatic islet beta-cells

OBJECTIVE: Carbohydrate-responsive element-binding protein (ChREBP) is a transcription factor that has been shown to regulate carbohydrate metabolism in the liver and pancreatic β-cells in response to elevated glucose concentrations. Because few genes have been identified so far as bona fide ChREBP-target genes, we have performed a genome-wide analysis of the ChREBP transcriptome in pancreatic β-cells. RESEARCH DESIGN AND METHODS: Chromatin immunoprecipitation and high-density oligonucleotide tiling arrays (ChIP-chip; Agilent Technologies) using MIN6 pancreatic β-cell extracts were performed together with transcriptional and other analysis using standard techniques. RESULTS: One of the genes identified by ChIP-chip and linked to glucose sensing and insulin secretion was aryl hydrocarbon receptor nuclear translocator (ARNT)/hypoxia-inducible factor-1β (HIF-1β), a transcription factor implicated in altered gene expression and pancreatic-islet dysfunction in type 2 diabetes. We first confirmed that elevated glucose concentrations decreased ARNT/HIF-1β levels in INS-1 (832/13) cells and primary mouse islets. Demonstrating a role for ChREBP in ARNT gene regulation, ChREBP silencing increased ARNT mRNA levels in INS-1 (832/13) cells, and ChREBP overexpression decreased ARNT mRNA in INS-1 (832/13) cells and primary mouse islets. We demonstrated that ChREBP and Max-like protein X (MLX) bind on the ARNT/HIF-1β promoter on the proximal region that also confers the negative glucose responsiveness. CONCLUSIONS: These results demonstrate that ChREBP acts as a novel repressor of the ARNT/HIF-1β gene and might contribute to β-cell dysfunction induced by glucotoxicity

Tissue-Resident Exhausted Effector Memory CD8 +

Experimental autoimmune uveoretinitis is a model for noninfectious posterior segment intraocular inflammation in humans. Although this disease is CD4(+) T cell dependent, in the persistent phase of disease CD8(+) T cells accumulate. We show that these are effector memory CD8(+) T cells that differ from their splenic counterparts with respect to surface expression of CD69, CD103, and Ly6C. These retinal effector memory CD8(+) T cells have limited cytotoxic effector function, are impaired in their ability to proliferate in response to Ag-specific stimulation, and upregulate programmed death 1 receptor. Treatment with fingolimod (FTY720) during the late phase of disease revealed that retinal CD8(+) T cells were tissue resident. Despite signs of exhaustion, these cells were functional, as their depletion resulted in an expansion of retinal CD4(+) T cells and CD11b(+) macrophages. These results demonstrate that, during chronic autoimmune inflammation, exhausted CD8(+) T cells become established in the local tissue. They are phenotypically distinct from peripheral CD8(+) T cells and provide local signals within the tissue by expression of inhibitory receptors such as programmed death 1 that limit persistent inflammation