Effects of nonnutritive sugar inclusion in laboratory diets and attracticidal spheres on survivorship and mobility of 2 Dipteran species, Rhagoletis pomonella (Diptera: Tephritidae) and Drosophila suzukii (Diptera: Drosophilidae).

Native apple maggot fly, Rhagoletis pomonella, and invasive spotted-wing drosophila, Drosophila suzukii, are key pests of apple and small fruit, respectively, in the United States. Both species are typically managed with standard insecticide applications. However, interest in alternative strategies that result in insecticide reductions has led to evaluations of nonnutritive sugars as toxicants for Drosophila species and development of attracticidal spheres for both species. Here, we evaluated the survivorship of R. pomonella and D. suzukii when provided with standard diets that substituted saccharin, sucralose, aspartame, erythritol, dextrose, or mannitol for the sucrose component and compared them with standard diets and water-only controls for up to 15 days. Presence of erythritol and mannitol significantly decreased survivorship of R. pomonella and erythritol significantly decreased the survivorship of D. suzukii. However, mobility trials following a 2 h exposure to aqueous solutions of each sugar treatment resulted in no strong impact on either species. Survivorship after 30 min exposure to erythritol or mannitol alone, or in combination with varying concentrations of sucrose (serving as a phagostimulant) at 30 min and 24 h were evaluated for both species. Only D. suzukii survivorship was affected with decreased survivorship on erythritol:sucrose solutions of 20:0% and 15:5% for 24 h. Based on all results, erythritol appeared most promising, and was integrated into attracticidal spheres as a toxicant but even at the highest concentration, survivorship remained unaffected for either species, thus making this nonnutritive sugar impractical and ineffective as a toxicant substitute in attracticidal spheres.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Effects of Myopia on Rates of Change in Optical Coherence Tomography Measured Retinal Layer Thicknesses in People with Multiple Sclerosis and Healthy Controls.

PURPOSE: To quantify the associations of myopia with longitudinal changes in retinal layer thicknesses in people with multiple sclerosis (PwMS) and healthy controls (HC). METHODS: A cohort of PwMS and HC with recorded refractive error (RE) prospectively scanned on Cirrus HD-OCT at the Johns Hopkins MS Center was assessed for inclusion. Exclusion criteria included OCT follow-up < 6 months, ocular comorbidities, incidental OCT pathologies, and inadequate scan quality. Eyes were classified as having high myopia (HM) (RE≤ -6 diopters), low myopia (LM) (RE> -6 and ≤ -3 diopters), or no myopia (NM) (RE> -3 and ≤ +2.75). Linear mixed-effects regression models were used in analyses. RESULTS: A total of 213 PwMS (eyes: 67 HM, 98 LM, 207 NM) and 80 HC (eyes: 26 HM, 37 LM, 93 NM) were included. Baseline average ganglion cell/inner plexiform (GCIPL) and peri-papillary retinal nerve fiber layer (pRNFL) thicknesses were lower in MS HM compared with MS NM (diff: -3.2 µm, 95% CI: -5.5 to -0.8, p = 0.008 and -5.3 µm, 95% CI: -9.0 to -1.7, p = 0.004, respectively), and similarly in HC HM, as compared with HC NM. Baseline superior, inferior, and nasal pRNFL thicknesses were lower in HM compared with NM, while temporal pRNFL thickness was higher, both in MS and HC (MS: 7.1 µm, 95% CI: 2.7-11.6, p = 0.002; HC: 4.7 µm, 95% CI: -0.3 to 9.7, p = 0.07). No longitudinal differences in rates of GCIPL change were noted between HM and LM vs. NM, either in MS or HC. CONCLUSION: Cross-sectional differences in average GCIPL and pRNFL thicknesses are commonly seen in people with HM as compared to reference normative values from people with NM and can lead to false attribution of pathology if RE is not taken into account. However, our study suggests that longitudinal changes in average GCIPL thickness in PwMS with myopia are similar in magnitude to PwMS with NM, and therefore are appropriate for monitoring disease-related pathology.

Risk Factors for Infection and Health Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic in People With Autoimmune Diseases.

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism.

The circulating metabolome provides unique insights into multiple sclerosis (MS) pathophysiology, but existing studies are relatively small or characterized limited metabolites. We test for differences in the metabolome between people with MS (PwMS; n = 637 samples) and healthy controls (HC; n = 317 samples) and assess the association between metabolomic profiles and disability in PwMS. We then assess whether metabolic differences correlate with changes in cellular gene expression using publicly available scRNA-seq data and whether identified metabolites affect human immune cell function. In PwMS, we identify striking abnormalities in aromatic amino acid (AAA) metabolites (p = 2.77E-18) that are also strongly associated with disability (p = 1.01E-4). Analysis of scRNA-seq data demonstrates altered AAA metabolism in CSF and blood-derived monocyte cell populations in PwMS. Treatment with AAA-derived metabolites in vitro alters monocytic endocytosis and pro-inflammatory cytokine production. We identify shifts in AAA metabolism resulting in the reduced production of immunomodulatory metabolites and increased production of metabotoxins in PwMS.

Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy.

BACKGROUND: Sphingosine-1-phosphate receptor (S1P) modulators and anti-CD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines. Relatively few studies have assessed the impact of an array of disease modifying therapies (DMTs) for multiple sclerosis (MS) on T cell immune responses to SARS-CoV-2 vaccination. METHODS: In 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-γ) (Mabtech, Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1µg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each). Plates were read on an AID iSpot Spectrum to determine the number of spot forming cells (SFC)/106 PBMCs. We tested for differences in immune responses across DMTs using linear models. FINDINGS: Humoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs. In a subset (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies. Anti-CD20 therapies were associated with an increase in IFN-γ SFC counts relative to those on no DMT or other DMTs (for anti-CD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for anti-CD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001). INTERPRETATION: We identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination. Follow up studies are needed to determine if this translates to protection against COVID-19 infection. FUNDING: This study was funded partially by 1K01MH121582-01 from NIH/NIMH and TA-1805-31136 from the National MS Society (NMSS) to KCF and TA-1503-03465 and JF-2007-37655 from the NMSS to PB. This study was also supported through the generosity of the collective community of donors to the Johns Hopkins University School of Medicine for COVID research.

Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy.

BACKGROUND: Sphingosine-1-phosphate receptor (S1P) modulators and antiCD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) for multiple sclerosis (MS) also impact T cell immune response to vaccination is unknown. METHODS: In 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-γ) (Mabtech,Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1µg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each). Plates were read on an AID iSpot Spectrum to determine number of spot forming cells (SFC)/10 6 PBMCs. We tested for differences in immune responses across DMTs using linear models. FINDINGS: Humoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs. In a subset with immune cell phenotyping (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies. AntiCD20 therapies were associated with an increase in IFN-γ SFC counts relative to those on no DMT or other DMTs (for antiCD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for antiCD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001). INTERPRETATION: We identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination. Follow up studies are needed to determine if this translates to protection against COVID-19 infection.

RISK FACTORS FOR INFECTION AND HEALTH IMPACTS OF THE COVID-19 PANDEMIC IN PEOPLE WITH AUTOIMMUNE DISEASES.

Background: People with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. Objective: Assess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care. Design: Longitudinal registry study. Participants: 4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns Hopkins. Measurements: Periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. Results: A total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption. Limitations: Results may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported. Conclusions: Exposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Multiple sclerosis management during the COVID-19 pandemic.

BACKGROUND: People with multiple sclerosis (MS) may be at higher risk for complications from the 2019 coronavirus (COVID-19) pandemic due to use of immunomodulatory disease modifying therapies (DMTs) and greater need for medical services. OBJECTIVES: To evaluate risk factors for COVID-19 susceptibility and describe the pandemic's impact on healthcare delivery. METHODS: Surveys sent to MS patients at Cleveland Clinic, Johns Hopkins, and Vall d'Hebron-Centre d'Esclerosi Múltiple de Catalunya in April and May 2020 collected information about comorbidities, DMTs, exposures, COVID-19 testing/outcomes, health behaviors, and disruptions to MS care. RESULTS: There were 3028/10,816 responders. Suspected or confirmed COVID-19 cases were more likely to have a known COVID-19 contact (odds ratio (OR): 4.38; 95% confidence interval (CI): 1.04, 18.54). In multivariable-adjusted models, people who were younger, had to work on site, had a lower education level, and resided in socioeconomically disadvantaged areas were less likely to follow social distancing guidelines. 4.4% reported changes to therapy plans, primarily delays in infusions, and 15.5% a disruption to rehabilitative services. CONCLUSION: Younger people with lower socioeconomic status required to work on site may be at higher exposure risk and are potential targets for educational intervention and work restrictions to limit exposure. Providers should be mindful of potential infusion delays and MS care disruption.

Pelagic larval duration predicts extinction risk in a freshwater fish clade.

Pelagic larval duration (PLD) can influence evolutionary processes ranging from dispersal to extinction in aquatic organisms. Using estimates of PLD obtained from species of North American darters (Percidae: Etheostomatinae), we demonstrate that this freshwater fish clade exhibits surprising variation in PLD. Comparative analyses provide some evidence that higher stream gradients favour the evolution of shorter PLD. Additionally, similar to patterns in the marine fossil record in which lower PLD is associated with greater extinction probability, we found a reduced PLD in darter lineages was evolutionarily associated with extinction risk. Understanding the causes and consequences of PLD length could lead to better management and conservation of organisms in our increasingly imperiled aquatic environments.

Fire promotes pollinator visitation: implications for ameliorating declines of pollination services.

Pollinators serve critical roles for the functioning of terrestrial ecosystems, and have an estimated annual value of over $150 billion for global agriculture. Mounting evidence from agricultural systems reveals that pollinators are declining in many regions of the world, and with a lack of information on whether pollinator communities in natural systems are following similar trends, identifying factors which support pollinator visitation and services are important for ameliorating the effects of the current global pollinator crisis. We investigated how fire affects resource structure and how that variation influences floral pollinator communities by comparing burn versus control treatments in a southeastern USA old-field system. We hypothesized and found a positive relationship between fire and plant density of a native forb, Verbesina alternifolia, as well as a significant difference in floral visitation of V. alternifolia between burn and control treatments. V. alternifolia density was 44% greater and floral visitation was 54% greater in burned treatments relative to control sites. When the density of V. alternifolia was experimentally reduced in the burn sites to equivalent densities observed in control sites, floral visitation in burned sites declined to rates found in control sites. Our results indicate that plant density is a proximal mechanism by which an imposed fire regime can indirectly impact floral visitation, suggesting its usefulness as a tool for management of pollination services. Although concerns surround the negative impacts of management, indirect positive effects may provide an important direction to explore for managing future ecological and conservation issues. Studies examining the interaction among resource concentration, plant apparency, and how fire affects the evolutionary consequences of altered patterns of floral visitation are overdue.