Regression calibration with instrumental variables for longitudinal models with interaction terms, and application to air pollution studies.

In this paper, we derive forms of estimators and associated variances for regression calibration with instrumental variables in longitudinal models that include interaction terms between two unobservable predictors and interactions between these predictors and covariates not measured with error; the inclusion of the latter interactions generalize results we previously reported. The methods are applied to air pollution and health data collected on children with asthma. The new methods allow for the examination of how the relationship between health outcome leukotriene E4 (LTE4, a biomarker of inflammation) and two unobservable pollutant exposures and their interaction are modified by the presence or absence of upper respiratory infections. The pollutant variables include secondhand smoke and ambient (outdoor) fine particulate matter. Simulations verify the accuracy of the proposed methods under various conditions.

GM-CSF Promotes Immune Response and Survival in a Mouse Model of COVID-19.

COVID-19 results in increased expression of inflammatory cytokines, but inflammation-targeting clinical trials have yielded poor to mixed results. Our studies of other disorders with an inflammatory component, including Alzheimer's disease, chemobrain, Down syndrome, normal aging, and West Nile Virus infection, showed that treatment with the 'pro-inflammatory' cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) in humans or mouse models alleviated clinical, behavioral, and pathological features. We proposed that human recombinant GM-CSF (sargramostim) be repurposed to promote both the innate and adaptive immune responses in COVID-19 to reduce viral load and mortality1. Here, we report the results of a placebo-controlled study of GM-CSF in human ACE2 transgenic mice inoculated intranasally with SARS-CoV2 virus, a model of COVID-19. Infection resulted in high viral titers in lungs and brains and over 85% mortality. GM-CSF treatment beginning one day after infection increased anti-viral antibody titers, lowered mean lung viral titers proportionately (p=0.0020) and increased the odds of long-term survival by up to 5.8-fold (p=0.0358), compared to placebo. These findings suggest that, as an activator of both the innate and adaptive immune systems, GM-CSF/sargramostim may be an effective COVID-19 therapy with the potential to protect from re-infection more effectively than treatment with antiviral drugs or monoclonal antibodies.

Altered plasma serine and 1-deoxydihydroceramide profiles are associated with diabetic neuropathy in type 2 diabetes and obesity.

Recent studies suggest that the accumulation of atypical, 1-deoxysphingolipids that lack the C1 hydroxyl group may be associated with diabetic neuropathy (DN). We hypothesized that specific plasma 1-deoxysphingolipids associate with DN severity, and that alterations in plasma serine and alanine associate with 1-deoxysphingolipid elevation in patients with type 2 diabetes (T2D). We examined individual 1-deoxysphingolipid species using LC/MS/MS in plasma samples from 75 individuals including lean controls (LC, n = 19), those with obesity (n = 19), obesity with T2D without DN (ob/T2D, n = 18), and obesity with T2D with DN (Ob/T2D/DN, n = 19). We observed a step wise increase in 1-deoxydihydroceramides across these four groups (spearman correlation coefficient r = 0.41, p = 0.0002). Mean total concentrations of 1-deoxydihydroceramides, and most individual 1-deoxydihydroceramide species, were higher in ob/T2D/DN versus LC group (8.939 vs. 5.195 pmol/100 µL for total 1-deoxydihydroceramides p = 0.005). No significant differences in 1-deoxydihydroceramides were observed between the ob/T2D and ob/T2D/DN groups. l-alanine was higher and l-serine lower in ob/T2D/DN versus LC groups (326.2 vs. 248.0 µM, p = 0.0086 and 70.2 vs. 89.8 µM, p = 0.0110), consistent with a potential contribution of these changes to the observed 1-deoxysphingolipids profiles. 1-deoxydihydroceramides correlated inversely with leg intraepidermal nerve fiber density (CC -0.40, p = 0.003). These findings indicate that 1-deoxydihydroceramides may be important biomarkers and/or mediators of DN.

The Multiple Sclerosis Severity Score: fluctuations and prognostic ability in a longitudinal cohort of patients with MS.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS), combining the Expanded Disability Status Scale (EDSS) and disease duration, attempts to stratify multiple sclerosis (MS) patients based on their rate of progression. Its prognostic ability in the individual patient remains unproven. OBJECTIVES: To assess the stability of MSSS within individual persons with MS in a longitudinal cohort, to evaluate whether certain factors influence MSSS variability, and to explore the ability of MSSS to predict future ambulatory function. METHODS: A single-center retrospective review was performed of patients following a single provider for at least 8 years. Mixed model regression modeled MSSS over time. A Kaplan-Meier survival plot was fitted, using change of baseline MSSS by at least one decile as the event. Cox modeling assessed the influence of baseline clinical and demographic factors on the hazard of changing MSSS by at least one decile. Linear models evaluated the impact of baseline EDSS, baseline MSSS, and other factors on the Timed 25-Foot Walk (T25FW). RESULTS: Out of 122 patients, 68 (55.7%) deviated from baseline MSSS by at least one decile. Final T25FW had slightly weaker correlation to baseline MSSS than to baseline EDSS, which was moderately strongly correlated with future log T25FW. CONCLUSION: Individual MSSS scores often vary over time. Clinicians should exercise caution when using MSSS to prognosticate.