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Abstract Rationale Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes, including asymptomatic infections, common colds, and severe lower respiratory illnesses. Objectives To identify factors that influence the severity of HRV illnesses. Methods HRV species and types were determined in 1,445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate to severe illnesses (MSI). Measurements and Main Results Altogether, 670 HRV infections were identified, and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of three species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and HRV-C (odds ratio, 7.6) were more likely to cause MSI compared with HRV-B. In addition, HRV infections were 5- to 10-fold more likely to cause MSI in the winter months (P < 0.0001) compared with summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (P = 0.004) were considered, strain-specific rates of HRV MSI ranged from less than 1% to more than 20%. Conclusions Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.

Abstract Rationale Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. Objective To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. Methods A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. Measurements and Main Results Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2–3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50–1.1). Conclusions Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.

Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. To determine whether rs6967330 influences RV-C infections and illnesses in early childhood. We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses. The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05-1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC (IRR = 1.89 [1.14-3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02-1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13-2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92-1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages. The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.

Abstract Rationale Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. Objectives To define the relationship between specific viral illnesses and early childhood asthma development. Methods A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase–polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. Measurements and Main Results Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR, 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. Conclusions Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.

For years, adult psychological research has benefitted from web-based data collection. There is growing interest in harnessing this approach to facilitate data collection from children and adolescents to address foundational questions about cognitive development. To date, however, few studies have directly tested whether findings from in-lab developmental psychology tasks can be replicated online, particularly in the domain of value-based learning and decision-making. To address this question, we set up a pipeline for online data collection with children, adolescents, and adults, and conducted a replication of Decker et al. (2016). The original in-lab study employed a sequential decision-making paradigm to examine shifts in value-learning strategies from childhood to adulthood. Here, we used the same paradigm in a sample of 151 children (N = 50; ages 8 - 12 years), adolescents (N = 50; ages 13 - 17 years), and adults (N = 51; ages 18 - 25 years) and replicated the main finding that the use of a “model-based” learning strategy increases with age. In addition, we adapted a new index of abstract reasoning (MaRs-IB; Chierchia et al. 2019) for use online, and replicated a key result from Potter et al. (2017), which found that abstract reasoning ability mediated the relation between age and model-based learning. Our re-analyses of two previous in-lab datasets alongside our analysis of our online dataset revealed few qualitative differences across task administrations. These findings suggest that with appropriate precautions, researchers can effectively examine developmental differences in learning computations through unmoderated, online experiments.

Chronic Inhibition of Circulating Dipeptidyl Peptidase IV by FE 999011 Delays the Occurrence of Diabetes in Male Zucker Diabetic Fatty Rats Béatrice Sudre 1 , Pierre Broqua 1 2 , Richard B. White 1 , Doreen Ashworth 2 , D. Michael Evans 2 , Robert Haigh 2 , Jean-Louis Junien 2 and Michel L. Aubert 1 1 Ferring Research Institute and Division of Biology of Growth and Reproduction, Department of Pediatrics, University of Geneva School of Medicine, Geneva, Switzerland 2 Ferring Research, Southampton, U.K. Abstract Acute suppression of dipeptidyl peptidase IV (DPP-IV) activity improves glucose tolerance in the Zucker fatty rat, a rodent model of impaired glucose tolerance, through stabilization of glucagon-like peptide (GLP)-1. This study describes the effects of a new and potent DPP-IV inhibitor, FE 999011, which is able to suppress plasma DPP-IV activity for 12 h after a single oral administration. In the Zucker fatty rat, FE 999011 dose-dependently attenuated glucose excursion during an oral glucose tolerance test and increased GLP-1 (7-36) release in response to intraduodenal glucose. Chronic treatment with FE 999011 (10 mg/kg, twice a day for 7 days) improved glucose tolerance, as suggested by a decrease in the insulin-to-glucose ratio. In the Zucker diabetic fatty (ZDF) rat, a rodent model of type 2 diabetes, chronic treatment with FE 999011 (10 mg/kg per os, once or twice a day) postponed the development of diabetes, with the twice-a-day treatment delaying the onset of hyperglycemia by 21 days. In addition, treatment with FE 999011 stabilized food and water intake to prediabetic levels and reduced hypertriglyceridemia while preventing the rise in circulating free fatty acids. At the end of treatment, basal plasma GLP-1 levels were increased, and pancreatic gene expression for GLP-1 receptor was significantly upregulated. This study demonstrates that DPP-IV inhibitors such as FE 999011 could be of clinical value to delay the progression from impaired glucose tolerance to type 2 diabetes. Footnotes Address correspondence and reprint requests to Dr. M.L. Aubert, Hôpital des Enfants, HUGs, 6 rue Willy-Donzé, 1211 Geneva 14, Switzerland. E-mail: michel.aubert{at}medecine.unige.ch . P.B., R.B.W., D.A., D.M.E., and R.H. are employed by, M.L.A. is a paid consultant for, and J.-L.J. is a former employee of Ferring Research Institute. Received for publication 6 November 2001 and accepted in revised form 19 February 2002. AFC, 7-amino-4-trifluoromethylcoumarin; DPP-IV, dipeptidyl peptidase IV; ELISA, enzyme-linked immunosorbent assay; FFA, free fatty acid; GIP, gastric inhibitory peptide; GLP, glucagon-like peptide; GLP-1R, GLP-1 receptor; IC 50 , half-maximal inhibitory concentration; IDGTT, intraduodenal glucose tolerance test; OGTT, oral glucose tolerance test; RT, reverse transcription; TG, triglyceride. DIABETES

Asthma is a chronic inflammatory disorder that affects more than 300 million people worldwide. Asthma management would benefit from additional tools that establish biomarkers to identify phenotypes of asthma. We present a microfluidic solution that discriminates asthma from allergic rhinitis based on a patient’s neutrophil chemotactic function. The handheld diagnostic device sorts neutrophils from whole blood within 5 min, and generates a gradient of chemoattractant in the microchannels by placing a lid with chemoattractant onto the base of the device. This technology was used in a clinical setting to assay 34 asthmatic (n = 23) and nonasthmatic, allergic rhinitis (n = 11) patients to establish domains for asthma diagnosis based on neutrophil chemotaxis. We determined that neutrophils from asthmatic patients migrate significantly more slowly toward the chemoattractant compared with nonasthmatic patients (P = 0.002). Analysis of the receiver operator characteristics of the patient data revealed that using a chemotaxis velocity of 1.55 μm/min for asthma yields a diagnostic sensitivity and specificity of 96% and 73%, respectively. This study identifies neutrophil chemotaxis velocity as a potential biomarker for asthma, and we demonstrate a microfluidic technology that was used in a clinical setting to perform these measurements.

Background Accurate positioning and programming of sacral neuromodulation (SNM) relies upon the use of several intraoperative and postoperative stimulation measurements. While the clinical utility of these acute measurements including pelvic floor motor thresholds (PFMT), toe/leg motor thresholds (TMT), and sensory thresholds (ST), are widely accepted, their usefulness in quantitative research remains unclear. The purpose of this prospective study was to test these measurements and gauge their utility in future research. Methods Eight participants received Axonics SNM, 6 Medtronic Interstim II, and 2 Medtronic Micro SNM. PFMT was measured after implantation. ST and the location of sensation (LOS) were measured immediately postoperatively (PO), at pre-release from the surgery center (PR), and during a follow-up clinic visit (FU). Thresholds were compared across contact and time using linear mixed-effects models. Results Significant differences in PFMT were found across electrode configurations, with stimulation through proximal contacts exhibiting lower PFMT than distal configurations. ST displayed no significant differences across electrodes and showed minimal changes over time. LOS exhibited substantial variability across patients and periods. Conclusions Results suggest that PFMT were able to differentiate differences across electrode configurations that may be useful for future quantitative research. The lack of differences in ST and LOS across electrode configurations was interesting given the focus on these measurements clinically. Future testing is to confirm these limitations.

In 2014, enterovirus D68 (EV-D68), previously associated primarily with mild respiratory illness, caused a large outbreak of severe respiratory illness and, in rare instances, paralysis. We compared the viral binding and replication of eight recent EV-D68 clinical isolates collected both before and during the 2014 outbreak and the prototype Fermon strain from 1962 in cultured HeLa cells and differentiated human primary bronchial epithelial cells (BEC) to understand the possible reasons for the change in virus pathogenicity. We selected pairs of closely related isolates from the same phylogenetic clade that were associated with severe vs. asymptomatic infections. We found no significant differences in binding or replication in HeLa cell cultures between the recent clinical isolates. However, in HeLa cells, Fermon had significantly greater binding (2–3 logs) and virus progeny yields (2–4 logs) but a similar level of replication (1.5–2 log increase in viral RNA from 2 h to 24 h post infection) compared to recent isolates. In differentiated BECs, Fermon and the recent EV-D68 isolates had similar levels of binding; however, the recent isolates produced 1.5–2-log higher virus progeny yields than Fermon due to increased replication. Interestingly, no significant differences in replication were identified between the pairs of genetically close recent EV-D68 clinical isolates despite the observed differences in associated disease severity. We then utilized RNA-seq to define the transcriptional responses in BECs infected with four recent EV-D68 isolates, representing major phylogenetic clades, and the Fermon strain. All the tested clinical isolates induced similar responses in BECs; however, numerous upregulated genes in antiviral and pro-inflammatory response pathways were identified when comparing the response to clinical isolates versus Fermon. These results indicate that the recent emergence in severe EV-D68 cases could be explained by an increased replication efficiency and enhanced inflammatory response induced by newly emerged clinical isolates; however, host factors are likely the main determinants of illness severity.