Recent Publications by CFE Educators

Delirium is a neurologic syndrome characterized by inattention and cognitive impairment frequently encountered in medically ill older adults. As a hallmark of age-related brain vulnerability, delirium offers a clinical model to investigate how peripheral immune responses contribute to acute brain dysfunction. Peripheral inflammation is a key trigger of delirium, but the patient-specific immune responses that drive delirium onset and recovery remain poorly understood. This retrospective cohort study of prospectively collected biospecimens examines RNA sequencing from peripheral blood mononuclear cells of adults hospitalized for COVID-19 to better understand patient-specific factors associated with delirium (n = 64). Longitudinal transcriptomic analyses highlight persistent immune dysregulation in delirium, marked by increasing expression trajectories of genes linked to innate immune pathways, including complement activation, cytokine production, and monocyte/macrophage recruitment. Genes involved adaptive immunity showed a declining trajectory over time in patients with delirium. Although corticosteroid treatment suppressed some aspects of immune hyperactivation, aberrant responses contributing to delirium were exacerbated. Delirium resolution was characterized by normalization of key transcripts such as CCL2 and innate immune markers. Novel associations with delirium included transcripts related to stress granule assembly and the T cell regulators DUSP2 and KLF10. Delirium in COVID-19 is associated with distinct and dynamic peripheral immune trajectories that are modulated by corticosteroids. Further understanding these mechanisms has important implications for preventing delirium in older adults. These findings provide novel mechanistic insights with translational relevance for immunomodulatory strategies targeting maladaptive immune responses to prevent or treat delirium in medically ill populations.

BACKGROUND

Chronic opioid use occurs in 25% of individuals with axial spondyloarthritis (axSpA). Whether introduction of tumor necrosis factor inhibitors (TNFi) influenced secular trends in opioid prescription in axSpA is unknown. We examined opioid prescription trends in axSpA, relative to nonsteroidal anti-inflammatory drugs (NSAIDs) and TNFi, using two observational databases.

METHODS

We used data from IQVIA Medical Research Database (IMRD), a UK electronic health records-based database from 2000-2020, and Merative™ MarketScan® (MarketScan), a US administrative claims-based database from 2006-2021. We included adults (18-89 years, IMRD; 18-65 years, MarketScan) with axSpA. We calculated annual prescription rates for opioids, NSAIDs and TNFi (only in MarketScan) and estimated percentage changes in annual prescription rates by medication class using joinpoint regression.

RESULTS

We included 1,689 individuals from IMRD (mean age 47 years; 74% male) and 18,858 individuals from MarketScan (mean age 45 years; 51% male). In IMRD, annual opioid prescription rates decreased by 2.5% (95% CI -9.1,1.9) between 2001-2007, increased by 3.9% (95% CI -3.0, 14.2) between 2007-2016, and decreased by 0.4% (95% CI -11.2, 2.9) between 2016-2020. In MarketScan, annual opioid prescription rates decreased by 1.5% (95% CI -3.0, 2.0) in 2008-2016 and decreased by 8.6% (95% CI -15.2, -5.7) in 2016-2021. TNFi prescriptions increased by 1.8% (95% CI 1.1, 2.5) in 2008-2021.

CONCLUSION

Opioid prescriptions rates remained stable over time in the UK, while they slightly decreased in the US as TNFi uptake increased. These trends may reflect a US nationwide change in guidance for opioid prescriptions issued in 2016.

OBJECTIVE

Entheses have been discussed as potential sources of pain in osteoarthritis (OA). Entheseal bone remodeling quantified by [18F]NaF-PET could be a surrogate marker for tensile forces causing a painful tissue response. This study aimed to investigate the relationship between [18 F]NaF-uptake, MRI findings and knee-related symptoms.

METHOD

Patients and healthy controls in this prospective observational study on patello-femoral OA (PFJOA) underwent simultaneous MR (at 3.0 T) and [18F]NaF PET imaging of both knees. Cartilage damage, subchondral marrow lesions, synovitis, and enthesophytes were semi-quantitatively assessed on MRI and entheseal tracer uptake was quantified in the anterior patella and tibial tuberosity. Symptoms were assessed with the Knee injury and Osteoarthritis Outcome Score (KOOS). Generalized estimating equations were used to investigate associations between tracer uptake and symptoms; analyses were additionally adjusted for MRI-detected changes (as alternative symptom drivers), age, sex and body mass index.

RESULTS

A total of 135 knees from 68 subjects were investigated (mean age 48.8 ± 10.4 years; 58.8% women). Higher [18F]NaF-uptake was significantly associated with worse outcomes for KOOS subscales sports (beta -2.7; p0.001), quality of live (beta 3.0; p0.001) and PFJ (beta 2.3; p=0.001), but not pain (beta -0.8; p=0.18), symptoms (beta -0.6; p=0.30) or activities of daily living (beta -1.1; p=0.06).

CONCLUSION

Entheseal bone remodeling quantified by [18F]NaF-PET-MRI is associated with patient-reported clinical knee outcomes. These findings underscore the potential of entheseal biology to inform the understanding of symptom generation in degenerative disease of the musculoskeletal system.