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Purpose: Evolving evidence demonstrates the role of epigenetics in the pathogenesis of osteoarthritis (OA), whereas in terms of mechanism, DNA methylation has received the highest attention thus far. This systematic review summarizes the current knowledge of DNA methylation and its influence on the pathogenesis of OA. Methods: A protocol in alignment with the PRISMA guidelines was employed to systematically review eight bibliographic databases between 1 January 2015 and 31 January 2021, to identify associations between DNA methylation and articular chondrocytes in OA. Results: We identified 23 gene-specific studies and 28 genome-wide methylation analyses. Gene-specific studies focused on pro-inflammatory markers in OA, demonstrating that DNA hypomethylation in the promoter region results in overexpression and hypermethylation is linked to gene silencing. Others reported on the association between OA risk genes and DNA methylation. Genome-wide methylation studies reported on differentially methylated regions (DMRs) comparing OA and non-OA chondrocytes. DMRs were seen in hip OA and knee OA chondrocytes. Conclusion: The current body of literature demonstrates the potential and crucial role of DNA methylation in the pathogenesis and progression of OA. This knowledge contributes to the understanding of the pathomechanisms behind OA at gene-specific and genome-wide levels. The observed differences in DNA methylation between healthy and diseased tissues indicate the occurrence of changes in DNA methylation. Based on this, future research in this field that explores the characteristics of potentially reversible changes in DNA methylation may lead to opportunities for causative treatment options for OA.

Muhammad B Qureshi,1 Jose O Garcia,1 Jaxon Quillen,2 Carolyn Mead-Harvey,2 Christina Wentz,3 Cherie B Nau,4 Muriel Schornack,4 Keith Baratz,4 Sanjay V Patel,4 Joanne Shen5 1Mayo Clinic Alix School of Medicine, Scottsdale, AZ, USA; 2Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA; 3Illinois College of Optometry, Chicago, IL, USA; 4Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA; 5Department of Ophthalmology, Mayo Clinic, Scottsdale, AZ, USACorrespondence: Joanne Shen, Department of Ophthalmology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, USA, 85259, Tel +1 480-301-8085, Fax +1 480-301-7326, Email shen.joanne@mayo.eduPurpose: To compare baseline characteristics and treatment of chronic ocular graft-versus-host disease (oGVHD) patients in two treatment locations.Patients and Methods: Patients diagnosed with definite chronic oGVHD between September 1, 2014 and September 20, 2021 at two locations were identified. IRB-approved retrospective chart review was conducted for the following data: demographic information, ocular surface disease index (OSDI), corneal fluorescein staining (CFS), and treatment(s) used. Differences by site were assessed using Pearson’s Chi-Square tests and two-sample t-tests; differences by time were assessed using paired t-tests.Results: At baseline, Clinic 1 (C1) patients had a worse mean OSDI score (47.8 vs 36.3, p = 0.011) and CFS in both OD (1.3 vs 0.8, p = 0.005) and OS (1.3 vs 0.6, p < 0.001) compared to Clinic 2 (C2). Comparing baseline to endpoint, C1 patients experienced an improvement in OSDI (− 17.26, p < 0.001), CFS OD (− 0.50, p < 0.001), and CFS OS (− 0.51, p < 0.001) at C1. Change in OSDI, CFS OD, or CFS OS was not statistically significant at C2. Despite similar follow-up length, C1 demonstrated more clinic visits (10.4 vs 3.4, p < 0.001) and more treatment trials (4.9 vs 2.4, p < 0.001) compared to C2. Punctal plugs (85.5% vs 61.2%, p = 0.002), punctal cautery (69.7% vs 28.6%, p < 0.001), topical steroids (72.4% vs 22.4%, p < 0.001), and autologous serum tears (AST) (52.6% vs 8.2%, p < 0.001) were used more frequently at C1 than at C2.Conclusion: oGVHD patients at C1 experienced significant improvement in OSDI and corneal fluorescein staining and compared to patients at C2, had more frequent follow-up and use of punctal plugs, punctal cautery, topical steroids, and AST.Keywords: graft-versus-host disease, GVHD, chronic GVHD, dry eye disease, ocular GVHD, keratoconjunctivitis sicca, KCS

IntroductionPhysical activity before COVID-19 infection is associated with less severe outcomes. The study determined whether a dose‒response association was observed and whether the associations were consistent across demographic subgroups and chronic conditions.MethodsA retrospective cohort study of Kaiser Permanente Southern California adult patients who had a positive COVID-19 diagnosis between January 1, 2020 and May 31, 2021 was created. The exposure was the median of at least 3 physical activity self-reports before diagnosis. Patients were categorized as follows: always inactive, all assessments at 10 minutes/week or less; mostly inactive, median of 0-60 minutes per week; some activity, median of 60-150 minutes per week; consistently active, median>150 minutes per week; and always active, all assessments>150 minutes per week. Outcomes were hospitalization, deterioration event, or death 90 days after a COVID-19 diagnosis. Data were analyzed in 2022.ResultsOf 194,191 adults with COVID-19 infection, 6.3% were hospitalized, 3.1% experienced a deterioration event, and 2.8% died within 90 days. Dose‒response effects were strong; for example, patients in the some activity category had higher odds of hospitalization (OR=1.43; 95% CI=1.26, 1.63), deterioration (OR=1.83; 95% CI=1.49, 2.25), and death (OR=1.92; 95% CI=1.48, 2.49) than those in the always active category. Results were generally consistent across sex, race and ethnicity, age, and BMI categories and for patients with cardiovascular disease or hypertension.ConclusionsThere were protective associations of physical activity for adverse COVID-19 outcomes across demographic and clinical characteristics. Public health leaders should add physical activity to pandemic control strategies.

BackgroundThe one-step membrane technique, using a human acellular dermal matrix (hADM), is an experimental method for treating large bone defects. This eliminates the need for the Masquelet membrane induction step, shortening the procedure while maintaining effectiveness. However, previous studies showed that colonizing hADM with bone marrow mononuclear cells (BMC) worsens healing, likely due to the presence of CD8+ lymphocytes, which negatively affect bone regeneration. This study aims to investigate whether the negative impact of BMC on bone healing in this technique is due to the CD8+ cell population.Materials and methodsA 5 mm femoral defect was created in 25 male Sprague-Dawley rats, divided into three groups (G1-G3). BMC were isolated from syngenic donor rats, with CD8+ lymphocytes removed magnetically from the BMC fraction in one group. The defects were filled with bone chips and wrapped with differently treated hADM: G1 received native hADM, G2 received hADM+BMC, and G3 received hADM+BMC-CD8. After 8 weeks, the femurs were evaluated through radiological, biomechanical, and histological examinations.ResultsBone defects and bone mineral density (BMD) were significantly improved in G3 (hADM+BMC-CD8) compared to G2 (hADM+BMC). Bone volume, bone formation, and median bending stiffness were higher in G3. Immunohistological analysis showed a significant decrease in CD8 cell count in G3, with a lower percentage of IFNγ-producing cells compared to G2.ConclusionDepleting CD8+ cells from BMC before colonizing hADM significantly improved bone healing, likely due to changes in the local mediator environment. This suggests that preoperative colonization with CD8+-depleted BMC could enhance the one-step membrane technique.

BackgroundRecent evidence links ambient air pollution to COVID-19 incidence, severity, and death, but few studies have analyzed individual-level mortality data with high quality exposure models.MethodsWe sought to assess whether higher air pollution exposures led to greater risk of death during or after hospitalization in confirmed COVID-19 cases among patients who were members of the Kaiser Permanente Southern California (KPSC) healthcare system (N=21,415 between 06-01-2020 and 01-31-2022 of whom 99.85 % were unvaccinated during the study period). We used 1 km resolution chemical transport models to estimate ambient concentrations of several common air pollutants, including ozone, nitrogen dioxide, and fine particle matter (PM2.5). We also derived estimates of pollutant exposures from ultra-fine particulate matter (PM0.1), PM chemical species, and PM sources. We employed Cox proportional hazards models to assess associations between air pollution exposures and death from COVID-19 among hospitalized patients.FindingsWe found significant associations between COVID-19 death and several air pollution exposures, including: PM2.5 mass, PM0.1 mass, PM2.5 nitrates, PM2.5 elemental carbon, PM2.5 on-road diesel, and PM2.5 on-road gasoline. Based on the interquartile (IQR) exposure increment, effect sizes ranged from hazard ratios (HR) = 1.12 for PM2.5 mass and PM2.5 nitrate to HR ∼ 1.06-1.07 for other species or source markers. Humidity and temperature in the month of diagnosis were also significant negative predictors of COVID-19 death and negative modifiers of the air pollution effects.InterpretationAir pollution exposures and meteorology were associated the risk of COVID-19 death in a cohort of patients from Southern California. These findings have implications for prevention of death from COVID-19 and for future pandemics.

PurposeWe evaluate the treatment effect of OC-01 (varenicline solution) nasal spray (VNS) in dry eye disease (DED) subjects from two randomized trials who self-reported autoimmune disease (AID).Patients and methodsPost hoc subgroup analysis of subjects reporting a history of AID from the integrated OC-01 VNS 0.03 or 0.06 mg and vehicle control (VC) treatment groups of the ONSET-1 and ONSET-2 trials. Mean change in Schirmer test with anesthesia score (STS, mm) and Eye Dryness Score (EDS) from baseline to 28 days was compared between OC-01 VNS and VC groups. Consistency of treatment effect in subjects with and without AID was evaluated using treatment-subgroup interaction terms in ANCOVA models for mean changes from baseline STS and EDS, and in a logistic regression model for proportion achieving ≥10 mm STS improvement.ResultsOf the 891 participants, 31 reported comorbid AID. In all models, the treatment-subgroup interaction terms were not significant (p>0.05), indicating consistency of therapeutic effect of OC-01 VNS in subjects with and without AID. In subjects with AID, the treatment difference for STS was 11.8 mm and -9.3 for EDS and difference for proportion of subjects with ≥10 mm STS improvement was 61.1%. The most common adverse event was sneeze (82-84%), graded as mild by 98% of subjects.ConclusionOC-01 VNS demonstrated consistency in improving both tear production and patient-reported symptoms in subjects with AID, consistent with pivotal ONSET-1 and 2 trial results. Further investigation is warranted, and results may further support use of OC-01 VNS for DED in AID patients.

Introduction: Streptococcus pneumoniae is the most common cause of bacterial meningitis and meningoencephalitis in humans. The bacterium produces numerous virulence determinants; among them, hydrogen peroxide (H2O2) and pneumolysin (Ply) contribute to bacterial cytotoxicity. Microglia, the resident phagocytes in the brain, are distinct from other macrophages, and we thus compared their susceptibility to pneumococcal toxicity and their ability to phagocytose pneumococci with those of bone-marrow-derived macrophages (BMDMs). Methods: Microglia and BMDMs were co-incubated with S. pneumoniae D39 to analyze the survival of phagocytes by fluorescence microscopy, bacterial growth by quantitative plating, and phagocytosis by an antibiotic protection assay. Ply was detected by hemolysis assay and Western blot analysis. Results: We found that microglia were killed during pneumococcal infection with a wild-type and an isogenic ply-deficient mutant, whereas the viability of BMDMs was not affected by pneumococci. Treatment with recombinant Ply showed a dose-dependent cytotoxic effect on microglia and BMDMs. However, high concentrations of recombinant Ply were required, and under the chosen experimental conditions, Ply was not detectable in the supernatant during infection of microglia. Inactivation of H2O2 by exogenously added catalase abolished its cytotoxic effect. Consequently, infection of microglia with pneumococci deficient for the pyruvate oxidase SpxB, primarily producing H2O2, resulted in reduced killing of microglia. Conclusion: Taken together, in the absence of Ply, H2O2 caused cell death in primary phagocytes in concentrations produced by pneumococci.