Background Asthma, a chronic inflammatory condition defined by episodic shortness of breath with expiratory wheezing and cough, is a serious health concern affecting more than 250 million persons. Genome-wide association studies have identified ORM (yeast)–like protein isoform 3 (ORMDL3) as a gene associated with susceptibility to asthma. Although its yeast ortholog is a negative regulator of de novo ceramide biosynthesis, how ORMDL3 contributes to asthma pathogenesis is not known. Objectives We sought to decipher the molecular mechanism for the pathologic functions of ORMDL3 in asthma and the relationship to its evolutionarily conserved role in regulation of ceramide homeostasis. Methods We determined the relationship between expression of ORMDL3 and ceramide in epithelial and inflammatory cells and in asthma pathogenesis in mice. Results Although small increases in ORMDL3 expression decrease ceramide levels, remarkably, higher expression in lung epithelial cells and macrophages in vitro and in vivo increased ceramide production, which promoted chronic inflammation, airway hyperresponsiveness, and mucus production during house dust mite–induced allergic asthma. Moreover, nasal administration of the immunosuppressant drug FTY720/fingolimod reduced ORMDL3 expression and ceramide levels and mitigated airway inflammation and hyperreactivity and mucus hypersecretion in house dust mite–challenged mice. Conclusions Our findings demonstrate that overexpression of ORMDL3 regulates ceramide homeostasis in cells in a complex manner and suggest that local FTY720 administration might be a useful therapeutic intervention for the control of allergic asthma.

Background Although telomere shortening occurs as a natural part of aging, there is now a robust body of research that suggests that there is a relationship between psychosocial, environmental, and behavioral factors and changes in telomere length. These factors need to be considered when integrating telomere measurement in biobehavioral research studies. Objectives This article provides a brief summary of the known facts about telomere biology and an integrative review of current human research studies that assessed relationships between psychosocial, environmental, or behavioral factors and telomere length. Methods An integrative review was conducted to examine human research studies that focused on psychosocial, environmental, and behavioral factors affecting telomere length and telomerase activity using the electronic databases PubMed/Medline and CINAHL from 2003 to the present. In addition to the known individual factors that are associated with telomere length, the results of the integrative review suggest that perceived stress, childhood adversities, major depressive disorder, educational attainment, physical activity, and sleep duration should also be measured. Discussion Multiple factors have been shown to affect telomere length. To advance understanding of the role of telomere length in health and disease risk, it will be important to further elucidate the mechanisms that contribute to telomere shortening.

Background The exciting discovery that telomere shortening is associated with many health conditions, and that telomere lengths can be altered in response to social and environmental exposures, has underscored the need for methods to accurately and consistently quantify telomere length. Objectives The purpose of this paper is to provide a comprehensive summary that compares and contrasts the current technologies used to assess telomere length. Discussion Multiple methods have been developed for the study of telomeres. These techniques include quantification of telomere length by terminal restriction fragmentation—which was one of the earliest tools used for length assessment—making it the gold standard in telomere biology. Quantitative-PCR provides the advantage of being able to use smaller amounts of DNA, thereby making it amenable to epidemiology studies involving large numbers of people. An alternative method uses fluorescent probes to quantify not only mean telomere lengths, but also chromosome-specific telomere lengths; however, the downside of this approach is that it can only be used on mitotically active cells. Additional methods that permit assessment of the length of a subset of chromosome-specific telomeres, or the subset of telomeres that demonstrate shortening, are also reviewed. Conclusion Given the increased utility for telomere assessments as a biomarker in physiological, psychological and biobehavioral research, it is important that investigators become familiar with the methodological nuances of the various procedures used for measuring telomere length. This will ensure that they are empowered to select an optimal assessment approach to meet the needs of their study designs. Gaining a better understanding of the benefits and drawbacks of various measurement techniques is important not only in individual studies, but also to further establish the science of telomere associations with biobehavioral phenomena.

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Background In patients with COVID-19, granulocyte-macrophage colony stimulating factor (GM-CSF) might be a mediator of the hyperactive inflammatory response associated with respiratory failure and death. We aimed to evaluate whether mavrilimumab, a monoclonal antibody to the GM-CSF receptor, would improve outcomes in patients with COVID-19 pneumonia and systemic hyperinflammation. Methods This investigator-initiated, multicentre, double-blind, randomised trial was done at seven hospitals in the USA. Inclusion required hospitalisation, COVID-19 pneumonia, hypoxaemia, and a C-reactive protein concentration of more than 5 mg/dL. Patients were excluded if they required mechanical ventilation. Patients were randomly assigned (1:1) centrally, with stratification by hospital site, to receive mavrilimumab 6 mg/kg as a single intravenous infusion, or placebo. Participants and all clinical and research personnel were masked to treatment assignment. The primary endpoint was the proportion of patients alive and off supplemental oxygen therapy at day 14. The primary outcome and safety were analysed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov , NCT04399980 , NCT04463004 , and NCT04492514 . Findings Between May 28 and Sept 15, 2020, 40 patients were enrolled and randomly assigned to mavrilimumab (n=21) or placebo (n=19). A trial of 60 patients was planned, but given slow enrolment, the study was stopped early to inform the natural history and potential treatment effect. At day 14, 12 (57%) patients in the mavrilimumab group were alive and off supplemental oxygen therapy compared with nine (47%) patients in the placebo group (odds ratio 1·48 [95% CI 0·43–5·16]; p=0·76). There were no treatment-related deaths, and adverse events were similar between groups. Interpretation There was no significant difference in the proportion of patients alive and off oxygen therapy at day 14, although benefit or harm of mavrilimumab therapy in this patient population remains possible given the wide confidence intervals, and larger trials should be completed. Funding Kiniksa Pharmaceuticals.

Introduction The purpose of this pilot study was to characterize the relationships among perceived stress, pain, fatigue, depression, anxiety, biomarkers and functional status in women with fibromyalgia syndrome (FMS) using a psychoneuroimmunological (PNI) framework. Materials and Methods Using a cross-sectional, correlational design, we asked 50 women diagnosed with FMS to complete the Perceived Stress Scale, Brief Pain Inventory, Brief Fatigue Inventory, Center for Epidemiological Studies-Depression scale, State-Trait Anxiety Inventory and Functional Impact Questionnaire. We analyzed plasma levels of 17 cytokines using a BioPlex® assay and levels of C-reactive protein (CRP) using a high-sensitivity ELISA assay. Results Compared to published guidelines (> 3 mg/L reflects high inflammation), CRP levels were elevated in participating women. Perceived stress demonstrated positive correlations with pain, fatigue, depression, anxiety and functional status and negative correlations with monocyte chemotactic protein-1(r = −0.30) and interleukin-1β (r = −0.29). Pain severity correlated with macrophage inflammatory protein-1β (r = 0.29), and pain interference negatively correlated with interleukin-1β (r = −0.30). Fatigue negatively correlated with interleukin-1β (r = −0.32), interleukin-10 (r = −0.31) and granulocyte colony stimulating factor (r = −0.31). Depressive symptoms correlated with CRP (r =0.31). Discussion Relationships among perceived stress and symptoms supported the PNI framework. Study findings are similar to previous studies showing that cytokines in persons with FMS do not show a consistent pattern. The elevated CRP levels suggest higher levels of generalized inflammation in the sample and provide evidence for continued development of biobehavioral interventions to address both symptoms and their biological markers over time.