Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB component Rela underpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss of Rela prevents development of Stat1-expressing CD4+ T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS-ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.

Alterations in brain TREM2 and Amyloid-ß levels are associated with neurocognitive impairment in HIV-infected persons on antiretroviral therapy.

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-ß, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aß protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aß levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aß in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aß and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Measurement tools for assessment of older age bipolar disorder: A systematic review of the recent global literature.

OBJECTIVES: More than 50% of people with bipolar disorder will be age 60 years or older by 2030. There is a need for more data to guide assessment and treatment in older age bipolar disorder (OABD); however, interpretation of findings from small, single-site studies may not be generalizable and there are few large trials. As a step in the direction of coordinated large-scale OABD data collection, it is critical to identify which measurements are currently used and identify potential gaps in domains typically assessed. METHODS: An international group of OABD experts performed a systematic literature review to identify studies examining OABD in the past 6 years. Relevant articles were assessed to categorize the types of clinical, cognitive, biomarker, and neuroimaging OABD tools routinely used in OABD studies. RESULTS: A total of 53 papers were identified, with a broad range of assessments. Most studies evaluated demographic and clinical domains, with fewer studies assessing cognition. There are relatively few biomarker and neuroimaging data, and data collection methods were less comprehensively covered. CONCLUSION: Assessment tools used in the recent OABD literature may help to identify both a minimum and a comprehensive dataset that should be evaluated in OABD. Our review also highlights gaps where key clinical outcomes have not been routinely assessed. Biomarker and neuroimaging assessment could be further developed and standardized. Clinical data could be combined with neuroimaging, genetic, and other biomarkers in large-scale coordinated data collection to further improve our understanding of OABD phenomenology and biology, thereby contributing to research that advances care.

Comparison of oral esomeprazole and oral omeprazole in the treatment of equine squamous gastric disease.

BACKGROUND: Oral omeprazole is the accepted treatment for equine squamous gastric disease (ESGD); however, it is not universally effective. Esomeprazole results in more consistent and pronounced acid suppression in men and is more effective than omeprazole in the treatment of oesophageal and gastric disease. Pharmacodynamic and pilot clinical studies have indicated esomeprazole might also be more effective than omeprazole in horses. OBJECTIVES: To compare the efficacy and safety of oral esomeprazole and omeprazole pastes in the treatment of ESGD and, where present, concurrent equine glandular gastric disease (EGGD). STUDY DESIGN: Randomised, single-blinded controlled trial. METHODS: Horses presenting with grade ≥2 ESGD lesions were randomly allocated to receive 4 mg/kg of either a buffered esomeprazole or omeprazole paste orally once daily for 28 days before gastroscopy being repeated within a further 3 days. Videos and images were anonymised and subsequently graded blind by one researcher. The severity of ESGD (and EGGD) lesions before and after treatment, and thereby treatment responses, were compared using univariable logistic regression. RESULTS: A higher proportion of horses had ESGD healing in response to esomeprazole treatment (63/74, 85%) than with omeprazole treatment (43/73, 59%) (odds ratio [OR]: 4.00, 95% confidence interval [CI]: 1.81, 8.82, p = 0.001). In a subset of horses that had concurrent EGGD, a greater proportion of the horses treated with esomeprazole had lesions ≤grade 1 (esomeprazole 28/51, 55%; omeprazole 6/24, 25%; OR: 3.65, 95% CI: 1.25, 10.71, p = 0.02) Using grade 0 as the benchmark for EGGD healing, the difference remained significant (OR: 4.44, 95% CI: 1.33, 14.85, p = 0.02). MAIN LIMITATIONS: It may not be possible to extrapolate these results to other populations with different signalment or management. CONCLUSIONS: Oral-buffered esomeprazole was a more effective treatment for ESGD (and concurrent EGGD) than oral-buffered omeprazole.

Evaluation of the treatment of equine glandular gastric disease with either long-acting-injectable or oral omeprazole.

BACKGROUND: Equine glandular gastric disease (EGGD) is common in domesticated horses and can be challenging to treat. Oral omeprazole (ORLO) is used widely but the clinical response is frequently poor. OBJECTIVES: To compare rates of EGGD healing and improvement between ORLO and a long-acting injectable omeprazole preparation (LAIO). STUDY DESIGN: Retrospective clinical study. METHODS: The case records and gastroscopy images of horses presenting to masked for peer review over a 12-month period were reviewed, with images blindly assessed by one of the authors. Treatment responses to 4 mg/kg LAIO administered every 7 days for 2 and 4 weeks were compared with ORLO 4 mg/kg PO q24hrs for 4 weeks. Data were compared using a Mann-Whitney U test with post-hoc Dunn's test, Chi-squared test and a Fisher's exact test. RESULTS: Thirty-three horses that received LAIO and 12 that received ORLO were identified. Nine horses in the LAIO had received other treatments previously. The groups were comparable in signalment and EGGD lesion severity. Long-acting injectable omeprazole was found to be non-inferior to ORLO. LAIO was associated with better healing rates than ORLO at 4 weeks (LAIO-80%; ORLO-42%; p = 0.02), and reduction in lesion severity at 2 and 4 weeks in the LAIO group but not in the ORLO group at 4 weeks. Eighteen percent of horses in the LAIO group and 50% in the ORLO group did not heal at 4 weeks. There was no association between rate of healing or improvement and resolution or improvement of clinical signs. Six localised and self-limiting injection site reactions were identified in 4 horses treated with LAIO (6.7%). MAIN LIMITATIONS: Retrospective design, small numbers and the use of other treatments prior to use of LAIO. CONCLUSIONS: LAIO was found to be non-inferior to oral omeprazole for EGGD. Larger blinded randomised clinical trials are justified.

Neuroprotection by the Ketogenic Diet: Evidence and Controversies.

The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.

COX2 regulates senescence secretome composition and senescence surveillance through PGE2.

Senescent cells trigger their own immune-mediated destruction, termed senescence surveillance. This is dependent on the inflammatory senescence-associated secretory phenotype (SASP), which includes COX2, an enzyme with complex roles in cancer. The role COX2 plays during senescence surveillance is unknown. Here, we show that during RAS-induced senescence (RIS), COX2 is a critical regulator of SASP composition and senescence surveillance in vivo. COX2 regulates the expression of multiple inflammatory SASP components through an autocrine feedback loop involving its downstream product, prostaglandin E2 (PGE2), binding to EP4. During in vivo hepatocyte RIS, Cox2 is critical to tumor suppression, Cxcl1 expression, and immune-mediated senescence surveillance, partially through PGE2. Loss of Cox2 in RIS dysregulates the intrahepatic immune microenvironment, with enrichment of immunosuppressive immature myeloid cells and CD4+ regulatory T lymphocytes. Therefore, COX2 and PGE2 play a critical role in senescence, shaping SASP composition, promoting senescence surveillance and tumor suppression in the earliest stages of tumorigenesis.

A study investigating the treatment of equine squamous gastric disease with long-acting injectable or oral omeprazole.

BACKGROUND: Equine squamous gastric disease (ESGD) is a highly prevalent disease in horses, particularly in elite athletes. Some horses respond slowly, or fail to respond, to the licensed treatment, oral omeprazole (ORLO). OBJECTIVES: To compare rates of ESGD healing and improvement between ORLO and a long-acting injectable omeprazole preparation (LAIO). STUDY DESIGN: Retrospective clinical study. METHODS: The case records and gastroscopy images of horses presenting to Rainbow Equine Hospital over a 12-month period were reviewed, with images being reviewed blind by one of the authors (David Rendle). Treatment responses were compared between horses that received 2 or 4 injections of 4 mg/kg LAIO at weekly intervals, and horses that received ORLO at 4 mg/kg PO SID for 4 weeks. Data were compared using a Mann-Whitney test with post hoc Dunn's test, chi-squared test or Fisher's exact test. RESULTS: Fifty-six horses met the inclusion criteria: 29 received LAIO and 27 received ORLO. Treatment groups were comparable in terms of signalment and ESGD lesions. There was a difference in rate of healing when LAIO and ORLO treatment groups were compared at 28 days (LAIO-97%; ORLO-67%; p = .005; OR = 14(1.8-158)), but no difference between LAIO at 14 days and ORLO at 28 days (LAIO-86%; ORLO-67%; p = .12; OR = 3.1 (0.9-10)). Five localised and self-limiting injection site reactions were identified in 3 horses out of 98 injections (5.1%). MAIN LIMITATIONS: The study was limited by its retrospective nature, absence of randomisation and limited numbers. CONCLUSIONS: Four weeks of treatment with LAIO resulted in better rates of ESGD healing than 4 weeks of ORLO. Larger more robust studies of LAIO are warranted.

Computed tomographic cervical myelography in horses: Technique and findings in 51 clinical cases.

BACKGROUND: Three-dimensional computed tomographic (CT) evaluation of the cervical vertebral column enables more accurate identification of osseous and soft tissue lesions than traditional latero-lateral radiography. However, examination of the complete cervical vertebral column has been limited by horse size, preventing evaluation of the caudal cervical vertebrae. OBJECTIVES: To describe a technique to enable CT myelography of the complete cervical spine and describe the findings in 51 horses. ANIMALS: Records of 51 horses presented for evaluation of cervical vertebral lesions. METHODS: A retrospective review of clinical records from all horses presented for CT myelography to further investigate possible cervical vertebral lesions was performed. A description of a novel approach to CT myelography in horses and retrospective review of the findings in clinical cases has been included. RESULTS: Degenerative joint disease was identified at 1 or more dorsal articular process joint in 50/51 horses, of which 44/51 had a site of grade 2 or greater. Spinal cord compression was observed on CT myelography in 31/51 horses, whereas attenuation of the dorsal contrast column was identified radiographically in 11/50 horses. Thirty-three horses showed narrowing or obliteration of the intervertebral foramina at 1 or more site and osteochondral fragments were seen in 11/51 horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Computed tomography myelography is relatively safe and an easily performed technique with the correct equipment, enabling evaluation of the cervical vertebral structures of horses in all planes and volumetrically. It is possible that lesion extent might be underestimated with this diagnostic modality, hence interpretation should be complimented with flexed and extended views radiographically.

Resting State Abnormalities of the Default Mode Network in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND: Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. OBJECTIVE: We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. METHODS: PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. RESULTS: Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. CONCLUSIONS: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.

A pilot of clinical performance indicators for suspected childhood epilepsies.

PURPOSE: In response to continuing concerns regarding the quality and equality of care for children and young people, the British Paediatric Neurology Association (BPNA) has supported the development of practical and meaningful audit to support quality improvement. METHOD: In 2006, the Children's Epilepsy Workstream in Trent (CEWT) coordinated a retrospective multi-service audit of paediatric epilepsy care against NICE and SIGN guidelines. This aimed to both facilitate quality improvements for participating services and act as a pilot for future potential national audits. RESULTS: The audit was achieved in 4 hospital services using prospective and retrospective ascertainment methods. 12 performance indicators were applied to each cohort. Overall 54% (12/22) of children with epilepsy had input from a paediatrician with "expertise" and 23% (5/22) had input from an epilepsy specialist nurse. CONCLUSION: Audit can be developed for epilepsies that delivers standardised quality metrics against national recommendations. As well as supporting local quality improvement initiatives, comparative and aggregate data can be produced to potentially give regional and national perspectives. The results and experience describe the journey towards the 2009-2012 Epilepsy 12 UK multicentre epilepsy audit.