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Low-income caregivers raising children with asthma experience many obstacles to their own health, including stress. To understand and describe their daily experiences, researchers conducted 40 qualitative interviews supplemented with descriptive quantitative surveys in Detroit, Michigan, as part of a community-based participatory research partnership of Community Action Against Asthma. Prevalence of chronic illness is noticeably higher among participants than the general US population. Caregivers identified stress processes that may influence disproportionate health outcomes and risk-related behaviors over their lifetime. Applying a life course perspective, findings suggest that public health interventions should address family-level comorbidities, increase instrumental social support, and acknowledge practical coping mechanisms. [ABSTRACT FROM AUTHOR]

This article describes the evaluation of a community-based participatory research (CBPR) community health worker (CHW) intervention to improve children's asthma-related health by reducing household environmental triggers for asthma. After randomization to an intervention or control group, 298 households in Detroit, Michigan, with a child, aged 7 to 11, with persistent asthma symptoms participated. The intervention was effective in increasing some of the measures of lung function (daily nadir Forced Expiratory Volume at one second [p = .03] and daily nadir Peak Flow [p = .02]), reducing the frequency of two symptoms ('cough that won't go away,' 'coughing with exercise'), reducing the proportion of children requiring unscheduled medical visits and reporting inadequate use of asthma controller medication, reducing caregiver report of depressive symptoms, reducing concentrations of dog allergen in the dust, and increasing some behaviors related to reducing indoor environmental triggers. The results suggest a CHW environmental intervention can improve children's asthma-related health, although the pathway for improvement is complex. [ABSTRACT FROM AUTHOR]

In a longitudinal cohort study of primary-school-age children with asthma in Detroit, Michigan, we examined relationships between lung function and ambient levels of particulate matter < or = 10 microm and < or = 2.5 microm in diameter (PM10 and PM2.5) and ozone at varying lag intervals using generalized estimating equations. Models considered effect modification by maintenance corticosteroid (CS) use and by the presence of an upper respiratory infection (URI) as recorded in a daily diary among 86 children who participated in six 2-week seasonal assessments from winter 2001 through spring 2002. Participants were predominantly African American from families with low income, and > 75% were categorized as having persistent asthma. In both single-pollutant and two-pollutant models, many regressions demonstrated associations between higher exposure to ambient pollutants and poorer lung function (increased diurnal variability and decreased lowest daily values for forced expiratory volume in 1 sec) among children using CSs but not among those not using CSs, and among children reporting URI symptoms but not among those who did not report URIs. Our findings suggest that levels of air pollutants in Detroit, which are above the current National Ambient Air Quality Standards, adversely affect lung function of susceptible asthmatic children. [ABSTRACT FROM AUTHOR]

Background: Lower airway enrichment with oral commensals has been previously associated with severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades and whether it is associated with a distinct host inflammatory endotype., Methods: Lower airway samples from 96 LT recipients were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods., Results: Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in moderate and severe PGD. Dirichlet multinomial mixtures modeling identified 2 distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD than no PGD were identified within the dysbiotic cluster (C-SPT, 48% and 29%, respectively) though this did not reach statistical significance (p = 0.06). PGD severity associated with increased BAL neutrophil concentration (p = 0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p < 0.05). Furthermore, signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p < 0.05). C-SPT exhibited differential expression of TNF, SERPINE1, MPO, and MMP1 genes and upregulation of MAPK pathways, host signling associated with neutrophilic inflammation., Conclusions: Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD. These data highlight a putative role of lower airway microbial dysbiosis in the pathogenesis of this syndrome., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Rationale: Acute cellular rejection (ACR) after lung transplant is a leading risk factor for chronic lung allograft dysfunction. Prior studies have demonstrated dynamic microbial changes occurring within the allograft and gut that influence local adaptive and innate immune responses. However, the lung microbiome's overall impact on ACR risk remains poorly understood. Objectives: To evaluate whether temporal changes in microbial signatures were associated with the development of ACR. Methods: We performed cross-sectional and longitudinal analyses (joint modeling of longitudinal and time-to-event data and trajectory comparisons) of 16S rRNA gene sequencing results derived from lung transplant recipient lower airway samples collected at multiple time points. Measurements and Main Results: Among 103 lung transplant recipients, 25 (24.3%) developed ACR. In comparing samples acquired 1 month after transplant, subjects who never developed ACR demonstrated lower airway enrichment with several oral commensals (e.g., Prevotella and Veillonella spp.) than those with current or future (beyond 1 mo) ACR. However, a subgroup analysis of those who developed ACR beyond 1 month revealed delayed enrichment with oral commensals occurring at the time of ACR diagnosis compared with baseline, when enrichment with more traditionally pathogenic taxa was present. In longitudinal models, dynamic changes in α-diversity (characterized by an initial decrease and a subsequent increase) and in the taxonomic trajectories of numerous oral commensals were more commonly observed in subjects with ACR. Conclusions: Dynamic changes in the lower airway microbiota are associated with the development of ACR, supporting its potential role as a useful biomarker or in ACR pathogenesis.

Objective: The purpose of this pilot study was to examine potential differences in motor competence (MC) and physical activity (PA) between children with and without asthma., Methods: Thirty-seven children and adolescents completed the Exercises for a Healthy Asthma Lifestyle and Enjoyment study (46% with asthma, 51% female, 11.1 ± 0.4 years, and 46% White). Motor competence was assessed using the Movement Assessment Battery for Children 2nd edition (MABC-2). PA was assessed using accelerometry., Results: Children with asthma had significantly lower MC in the domain of aiming and catching (with asthma: 8.2 ± 0.4 vs. without asthma: 9.9 ± 0.5; p  = 0.03) and fewer daily minutes spent in moderate-to-vigorous PA (MVPA) (with asthma: 18.0 ± 2.3 min vs. without asthma: 27.2 ± 3.6 min; p  = 0.047). There were no significant group differences in manual dexterity, balance, total MABC-2 score, or total daily PA (all p s > 0.05)., Conclusions: This study provides confirmatory evidence that children with asthma display lower MC and spend less time in MVPA compared to children without asthma. Because MC is a prerequisite for engaging in PA, future research should seek to determine if the differences observed in MC contribute to disparities in MVPA observed in this clinical population.

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID 50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID 50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 ., (© 2023. The Author(s).)

Purpose: The purpose of this study was to examine the psychological responses to intermittent activities of varying intensities and types among children with and without asthma., Methods: A total of 37 children and adolescents (51% male, aged 8-16 y, 54% nonwhite, and 54% without asthma) participated in this study. Participants completed 5 exercises in the same order: self-paced walking, resistance activities, dance video, gamified obstacle course, and step test. In-task mood was assessed using the Feeling Scale, in-task perceived exertion was assessed via the ratings of perceived exertion scale, and postactivity enjoyment was assessed using the Physical Activity Enjoyment Scale., Results: There was a significant main effect of exercise type on mood (P < .001), ratings of perceived exertion (P < .001), and enjoyment (P < .002). There was not a significant main effect of asthma status on mood, ratings of perceived exertion, or enjoyment (Ps > .05). Children with asthma reported significantly lower in-task mood during the step exercise (P < .037) and reported significantly lower postactivity enjoyment after the walk and obstacle course exercises (Ps < .03)., Conclusions: Regardless of differences by asthma status for in-task mood during the obstacle course and for postactivity enjoyment during the walk and step exercises, both children with and without asthma reported high in-task mood and postactivity enjoyment during all 5 exercises.

Competing Interests: Disclosure: The authors have no conflicts of interest to report. There was no funding associated with this research.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n = 21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8 weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n = 21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4% vs. 85.7%, P = .17) or rejection requiring treatment (33.3% vs. 57.1%, P = .12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD ± .37], P = .67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P = .09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P = .14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Children with asthma often experience physical activity (PA) induced symptoms 5-15 min following the start of exercise. Classroom PA breaks provide short intermittent bouts of PA and may represent a novel strategy to safely promote PA participation in this clinical population. The purpose of this study was to determine the feasibility of a classroom-based PA intervention, Interrupting Prolonged Sitting with Activity (InPACT), where teachers implement 5 × 4-min moderate-to-vigorous physical activity (MVPA) breaks throughout the school day. Nine classrooms at one elementary-middle school in Detroit, MI (student demographics: 79% Hispanic; 80% on free/reduced lunch; 31% prevalence of asthma and asthma-like symptoms) participated in this 20-week intervention. Asthma status was self-reported via the International Study of Asthma and Allergies in Childhood (ISAAC) Video Questionnaire in conjunction with nurse documentation. PA participation, exercise intensity, and asthmatic symptom occurrence were assessed via direct observation. Students accumulated approximately 17 min of activity per day during PA breaks. Compared to students without asthma, a higher percentage of students with asthma participated in MVPA (asthma: 52.9% ± 1.2%; non-asthma: 46.2% ± 0.8%; p = 0.01), a lower percentage participated in light PA (asthma: 25.9% ± 1.0%; non-asthma: 30.1% ± 0.7%; p = 0.01), and sedentary time during activity breaks (asthma: 21.2% ± 0.9%; non-asthma: 23.8% ± 0.7%; p = 0.02). Out of 294 observations, six instances of asthmatic symptoms (coughing) were observed in students with asthma 5-15 min following the PA break. Symptoms self-resolved within 15-min of the PA break and did not result in sustained exercise-induced bronchoconstriction. Classroom-based interventions that incorporate short intermittent bouts of PA represent safe exercises for children with asthma and may help to reduce PA disparities in this clinical population., (© 2022. Society for Prevention Research.)

Pump thrombosis remains a feared complication for patients implanted with durable left ventricular assist devices. Optimal treatment is unknown, but consists of either pharmacologic fibrinolysis or surgical pump exchange. Fibrinolysis is less invasive, but carries a significant risk of intracerebral hemorrhage. We present four cases of LVAD pump thrombosis successfully treated with a novel protocol that consists of low-dose four-factor prothrombin complex concentrate to reverse baseline INR elevation prior to alteplase administration to minimize the risk for intracerebral hemorrhage.

Bleeding following cardiac surgery that warrants transfusion of blood products is associated with significant complications, including increased mortality at 1 year following surgery. Factor concentrates, such as prothrombin complex concentrate (PCC), or recombinant activated factor VII (rFVIIa) have been used off-label for bleeding in cardiac surgery that is refractory to conventional therapy. The objective of this retrospective study is to assess the hemostatic effectiveness of 4-factor PCC or rFVIIa for bleeding after a broad range of cardiac surgeries. Patients were included if they were at least 18 years of age and had undergone cardiac surgery with bleeding requiring intervention with 4-factor PCC or rFVIIa. There were no differences observed in the number of packed red blood cells (4-factor PCC: 2 units vs. rFVIIa: 2 units), fresh frozen plasma (0 units vs. 1 unit) or platelet (2 units vs. 2 units) transfusions following the administration of 4-factor PCC or rFVIIa. The patients in the rFVIIa group, required more cryoprecipitate than those in the 4-factor PCC group (4-factor PCC: 2 units (range 0-6) vs. rFVIIa: 2 units (range 0-8), p = 0.03). There were no differences in secondary outcomes of chest tube output at 2, 6, 12 and 24 hours, nor was there a difference in reexploration rates or the median length of stay in the intensive care unit. Thromboembolic complications at 30 days were similar between the two groups (4-factor PCC: 13% vs. rFVIIa 26%, p = 0.08). The total median dose requirement for 4-factor PCC was 1000 units (15 units/kg) and 2 mg (20 mcg/kg) for rFVIIa. The results demonstrate feasibility of utilizing the minimum amount of drug in order to achieve a desired effect. Both 4-factor PCC and rFVIIa appear to be safe and effective options for the management of bleeding associated with cardiac surgery.

Opioid analgesics are commonly used post-lung transplant, but have many side effects and are associated with worse outcomes. We conducted a retrospective review of all lung transplant recipients who were treated with a multimodal opioid-sparing pain protocol. The use of liposomal bupivacaine intercostal nerve block was variable due to hospital restrictions. The primary objective was to describe opioid requirements and patient-reported pain scores early post-lung transplant and to assess the impact of intraoperative liposomal bupivacaine intercostal nerve block. We treated 64 lung transplant recipients with our protocol. Opioid utilization decreased to a mean of 43 milligram oral morphine equivalents by postoperative day 4. Median pain scores peaked at 4 on postoperative day 1 and decreased thereafter. Only three patients were discharged home with opioids, all of whom were taking opioid agonist therapy pre-transplant for opioid use disorder. Patients who received liposomal bupivacaine intercostal nerve block in the operating room had a significant reduction in opioid consumption over postoperative day 1 through 4 (228 mg vs. 517 mg, P= .032). A multimodal opioid-sparing pain management protocol is feasible and resulted in weaning of opioids prior to hospital discharge., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with cardiogenic shock after percutaneous coronary intervention (PCI) may require mechanical circulatory support (MCS). The combination of dual antiplatelet therapy with cangrelor and continuous anticoagulation required for MCS may increase the risk of bleeding., Objective: The objective of the study is to describe the complications and outcomes of patients who received cangrelor during MCS following PCI., Methods: This is a single-center, retrospective, observational case series of 17 patients who received cangrelor while on MCS from June 2017 to September 2019., Results: In a case series of 17 patients, 8 patients (47%) were supported with an Impella device and 4 patients (24%) with venoarterial (VA) extracorporeal membrane oxygenation (ECMO); 5 required (29%) concomitant VA ECMO and Impella support in the setting of cardiogenic shock. All patients received triple antithrombotic therapy with aspirin, heparin, and cangrelor. Cangrelor was commonly initiated at a median dose of 0.75 (range 0.5-4) µg/kg/min. Cangrelor dose adjustments included changes in increments up to 0.25 µg/kg/min with review of P2Y12 levels. A total of 10 patients (59%) experienced a bleeding event, most commonly located at the peripheral cannulation site (40%) and in the gastrointestinal tract (30%). Seven (70%) and 3 (30%) of the bleeding complications were classified as major and minor, respectively. No patient developed in-stent thrombosis during the hospitalization; 14 (82%) patients survived their MCS course., Conclusion and Relevance: This case series suggests that cangrelor doses less than 0.75 µg/kg/min may be beneficial. Larger studies should evaluate alternative dosing regimens.

Transplanting hepatitis C viremic donor organs into hepatitis C virus (HCV)-negative recipients is becoming increasingly common; however, practices for posttransplant direct-acting antiviral (DAA) treatment vary widely. Protracted insurance authorization processes for DAA therapy often lead to treatment delays., Methods: At our institution, 2 strategies for providing DAA therapy to HCV - recipients of HCV + transplants have been used. For thoracic organ recipients, an institution-subsidized course of initial therapy was provided to ensure an early treatment initiation date. For abdominal organ recipients, insurance approval for DAA coverage was sought once viremia developed, and treatment was initiated only once the insurance-authorized supply of drug was received. To evaluate the clinical impact of these 2 strategies, we retrospectively collected data pertaining to the timing of DAA initiation, duration of recipient viremia, and monetary costs incurred by patients and the institution for patients managed under these 2 DAA coverage strategies., Results: One hundred fifty-two transplants were performed using HCV viremic donor organs. Eighty-nine patients received DAA treatment without subsidy, and 62 received DAA treatment with subsidy. One patient who never developed viremia posttransplant received no treatment. Subsidizing the initial course enabled earlier treatment initiation (median, 4 d [interquartile range (IQR), 2-7] vs 10 [IQR, 8-13]; P  < 0.001) and shorter duration of viremia (median, 16 d [IQR, 12-29] vs 36 [IQR, 30-47]; P  < 0.001). Institutional costs averaged $9173 per subsidized patient and $168 per nonsubsidized patient. Three needlestick exposures occurred in caregivers of viremic patients., Conclusions: Recipients and their caregivers stand to benefit from earlier DAA treatment initiation; however, institutional costs to subsidize DAA therapy before insurance authorization are substantial. Insurance authorization processes for DAAs should be revised to accommodate this unique patient group., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: There is a lack of robust data evaluating outcomes of enoxaparin "bridge" therapy in left ventricular assist device (LVAD) patients., Methods: We performed a retrospective study of HeartMate II (HM II) and HeartWare HVAD recipients that received therapeutic enoxaparin as "bridge" therapy to describe bleeding and thrombotic events and compare outcomes between devices. The primary endpoint was the incidence of bleeding within 30 days of "bridge" episode. Major bleeding was defined by INTERMACS criteria., Results: We evaluated 257 "bridge" episodes in 54 patients, 35 with a HM II device and 19 with an HVAD device that underwent 176 and 81 bridging episodes, respectively. The median INR prior to "bridge" was lower in the HM II group compared to the HVAD group (1.5 vs 1.7, P < .01), however, there was no difference in the median duration of "bridge" therapy (7 vs 7 days, P = .42). There were a total of 30 (12%) bleeding episodes, with the majority in the HM II group vs HVAD (26 [15%] vs 4 [5%], P = .02). We observed 3 (1%) thromboembolic events in 2 (4%) patients with an HVAD device. On multivariate analysis, the presence of a HM II device was associated with a 4-fold increased risk of bleeding., Conclusion: We found the use of enoxaparin "bridge" therapy to be associated with a higher incidence of bleeding in patients with a HM II device compared with an HVAD device. Assessment of device- and patient-specific factors should be evaluated to minimize bleeding events.

Hemoadsorption with CytoSorb has been used as an adjunct in the treatment of severe coronavirus disease 2019 (COVID-19)-related respiratory failure. It remains unknown if CytoSorb hemoadsorption will alter sedative and analgesic dosing in critically ill patients on venovenous extracorporeal membrane oxygenation (VV-ECMO). We conducted a retrospective review of patients with severe COVID-19 requiring VV-ECMO for respiratory support. Patients who were enrolled in a clinical study of CytoSorb were compared with patients on VV-ECMO alone. Data were collected for the 72-hour CytoSorb therapy and an additional 72 hours post-CytoSorb, or a corresponding control time period. Sedative and analgesic doses were totaled for each day and converted to midazolam or fentanyl equivalents, respectively. The primary endpoint, change in sedative and analgesic requirements over time, were compared using a two-way mixed analysis of variance. Of the 30 patients cannulated for VV-ECMO for COVID-19, 4 were excluded, leaving 8 patients in the CytoSorb arm and 18 in the Control. There was no effect of CytoSorb therapy on midazolam equivalents over the 72-hour therapy (p = 0.71) or the 72 hours post-CytoSorb (p = 0.11). In contrast, there was a significant effect of CytoSorb therapy on fentanyl equivalents over the first 72 hours (p = 0.01), but this was not consistent over the 72-hours post-CytoSorb (p = 0.23). CytoSorb therapy led to significant increases in analgesic requirements without impacting sedative requirements. Further research is needed to define the relevance of CytoSorb hemoadsorption on critical care pharmacotherapy., Competing Interests: Disclosure: Dr. Moazami serves on a research committee for CytoSorbent and is an investigator with Medtronic. The remaining authors have disclosed that they have no conflicts of interest relevant to this research. There was no funding associated with this research., (Copyright © ASAIO 2021.)

Background: Rhinovirus (RV) is the main cause of asthma exacerbations in children. Some studies reported that persons with asthma have attenuated interferon (IFN) responses to experimental RV infection compared with healthy individuals. However, responses to community-acquired RV infections in controls and children with asthma have not been compared., Objective: To evaluate nasal cytokine responses after natural RV infections in people with asthma and healthy children., Methods: We compared nasal cytokine expression among controls and children with asthma during healthy, virus-negative surveillance weeks and self-reported RV-positive sick weeks. A total of 14 controls and 21 patients with asthma were studied. Asthma disease severity was based on symptoms and medication use. Viral genome was detected by multiplex polymerase chain reaction. Nasal cytokine protein levels were determined by multiplex assays., Results: Two out of 47 surveillance weeks tested positive for RV, illustrating an asymptomatic infection rate of 5%. A total of 38 of 47 sick weeks (81%) tested positive for the respiratory virus. Of these, 33 (87%) were positive for RV. During well weeks, nasal interleukin 8 (IL-8), IL-12, and IL-1β levels were higher in children with asthma than controls. Compared with healthy virus-negative surveillance weeks, IL-8, IL-13, and interferon beta increased during colds only in patients with asthma. In both controls and children with asthma, the nasal levels of interferon gamma, interferon lambda-1, IL-1β, IL-8, and IL-10 increased during RV-positive sick weeks. During RV infection, IL-8, IL-1β, and tumor necrosis factor-α levels were strongly correlated., Conclusion: In both controls and patients with asthma, natural RV infection results in robust type II and III IFN responses., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

To determine the impact of tocilizumab, a monoclonal antibody against the interleukin 6 receptor, on survival in patients with coronavirus disease 2019., Design: Observational cohort study of patients hospitalized with coronavirus disease 2019 between March 1, 2020, and April 24, 2020. A propensity-matched (1:1) analysis was used to compare patients who received tocilizumab to controls who did not. Competing risk survival analysis was used to determine the primary outcome of time to mortality, and adjusted log-linear and logistic regression for secondary outcomes., Setting: Three hospitals within the NYU Langone Health system in New York., Patients: Consecutive adult patients hospitalized with coronavirus disease 2019., Intervention: Tocilizumab 400-mg IV once in addition to standard of care or standard of care alone., Measurements and Main Results: Data from 3,580 severe acute respiratory syndrome coronavirus 2 positive qualifying hospitalized patients were included, of whom 497 (13.9%) were treated with tocilizumab. In the analysis of tocilizumab-treated patients and matched controls, fewer tocilizumab-treated patients died (145/497, 29.2%) than did controls (211/497, 42.4%). In the adjusted competing risk regression model, tocilizumab therapy was associated with improved survival relative to controls (hazard ratio = 0.24, 95% CI = 0.18-0.33, p < 0.001). Tocilizumab-treated patients and controls had similar adjusted time to discharge from hospital (hazard ratio = 0.96, 95% CI = 0.78-1.17, p = 0.67). However, they had longer adjusted ICU length of stay (rate ratio = 3.1, 95% CI = 2.5-3.7, p < 0.001) and a higher adjusted infection rate (odds ratio = 4.18, 95% CI = 2.72-6.52, p < 0.001) than controls., Conclusions: Tocilizumab therapy was associated with significantly improved survival in coronavirus disease 2019 patients. This survival benefit was associated with increased ICU length of stay and increased infection rate, even as more patients in the tocilizumab group were rescued from rapid death. A prospective, randomized, placebo-controlled trial is needed to confirm these findings., Competing Interests: Dr. Montgomery has served on an advisory board for Viela Bio/CTI, CSL Behring, eGenesis, RMEI, Takeda, and Regeneron. He has received research funding from HANSA Biopharma. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

We conducted a retrospective review of thoracic transplant recipients (22 heart and 16 lung transplant recipients) prospectively enrolled in a single-center observational study of HCV NAT+ organ transplantation in HCV NAT- recipients. All recipients were treated with 8 weeks of glecaprevir-pibrentasvir (GP) for HCV viremia in addition to standard triple immunosuppression post-transplant. Thoracic transplant recipients of HCV NAT- organs were used as a control (24 heart and 22 lung transplant recipients). Our primary outcome was to assess the effect of GP on tacrolimus dose requirements. Secondary objectives included assessing drug interactions with common post-transplant medications, adverse effects, and the need to hold or discontinue GP therapy. The median tacrolimus concentration-to-dose ratio (CDR) in the cohort was 184 (99-260) during GP therapy and 154 (78-304) over the first month after GP (P = .79). Trends in median tacrolimus CDR were similar on a per-week basis and per-patient basis. In three instances, concomitant posaconazole and GP led to hyperbilirubinemia and interruption of posaconazole. GP therapy was held in one heart transplant recipient and discontinued in another due to unresolving hyperbilirubinemia. Utilization of GP to treat HCV viremia post-thoracic transplant is feasible and safe, but requires modifications to post-transplant pharmacotherapy and careful monitoring for adverse effects., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

During the holy month of Ramadan, Muslims fast from all water, food, and medications from dawn till dusk. To date, the existing medical literature focuses on adult fasting with little attention paid to pediatric fasting practices. An anonymous, digital, bilingual survey was conducted using Qualtrics software. Participants were recruited in-person at various community clinics, businesses, and mosques as well as online via social media. To be eligible for the study, participants must identify as Muslim and be parents or guardians of child/ren between the age/s of 7 and 18. Between July 2017 and May 2018, 918 people took part in the initial survey, with 70% (524/751) of participants living in Wayne County, MI. Approximately 80% (624/779) identified as Arab American and 57% (437/773) as immigrants to the US. Over 63% (522/827) of participants reported that their child's health care provider was unaware that their child/ren fasted during Ramadan. In addition, 75% (613/820) of participants indicated that their child's health care provider did not offer them any medical advice regarding fasting. However, 69% (554/805) of participants reported being comfortable discussing fasting practices with their child's doctor. Furthermore, 80% (569/714), of participants reported that their child/ren's doctor had a good or an advanced understanding of fasting. Our study is an important first step in helping elucidate beliefs and practices about Muslim pediatric fasting in Michigan. In addition, it highlights a stark contrast between the perceptions of parents and the current clinical practice of their physicians.

Community-based participatory research (CBPR) is an equitable partnership approach that links academic researchers, community organizations, and public health practitioners to work together to understand and address health inequities. Although numerous educational materials on CBPR exist, few training programs develop the skills and knowledge needed to establish effective, equitable partnerships. Furthermore, there are few professional development opportunities for academic researchers, practitioners, and community members to obtain these competencies in an experiential co-learning process. In response, the Detroit Community-Academic Urban Research Center developed the CBPR Partnership Academy, an innovative, yearlong capacity-building program facilitated by experienced community and academic partners, involving an intensive short course, partnership development, grant proposal preparation and funding, mentoring, online learning forums, and networking. Three diverse cohorts (36 teams) from 18 states and 2 tribal nations have participated. We describe the rationale and components of the training program and present results from the first two cohorts. Evaluation results suggest enhanced competence and efficacy in conducting CBPR. Outcomes include partnerships established, grant proposals submitted and funded, workshops and research conducted, and findings disseminated. A community-academic partner-based, integrated, applied program can be effective for professional development and establishing innovative linkages between academics and practitioners aimed at achieving health equity.

Background: There is a clear relationship between obesity and asthma, with obesity recognized as a risk factor for asthma. There is mounting evidence, however, that asthma may predict obesity risk via behavioral pathways. Objectives: The purpose of this study was to assess the cross-sectional relationships between asthma, body mass index (BMI) percentile, and behavioral factors including caloric intake, dietary inflammatory index, moderate-vigorous physical activity (MVPA), and sedentary time (SED) among African American adolescents. Methods: A community-based sample of 195 African American youth (ages 11-18 years) were included in this analysis. Asthma status was based on self-report using the International Study of Asthma and Allergies in Children's Phase Three questionnaire. MVPA and SED were measured via accelerometry, and caloric intake and dietary inflammatory index were evaluated with the Food Frequency Questionnaire. Weight status was assessed via BMI percentile using measured weight, height, and CDC growth charts. Results: Adolescents with a history of asthma were significantly more overweight (62% vs. 43%, p  = 0.04) and consumed a higher inflammatory diet (1.6 ± 0.3 vs. 1.0 ± 0.2, p  = 0.02) than their peers who never had asthma. After adjusting for all covariates, activity and dietary variables, odds ratio analysis revealed adolescents who reported ever having asthma were 3.1 ± 1.5 times as likely to be overweight or obese than adolescents with no asthma history ( p  = 0.02). Conclusions: Presence of asthma history was associated with increased obesity risk in African American adolescents, independent of behavioral factors. Longitudinal studies are needed to better understand the relationship between asthma and obesity in African American adolescents.

The approach to monitoring anticoagulation in adult patients receiving heparin on extracorporeal membrane oxygenation (ECMO) support is controversial. The objective of this study was to compare the correlation between anti-Xa and activated partial thromboplastin time (aPTT) with heparin dose and to describe their association with clinical events in adult ECMO patients. We conducted a retrospective single-center study of 34 adult ECMO patients whose heparin was monitored by anti-Xa and/or aPTT. The heparin dose-to-assay correlation coefficient was 0.106 for aPTT and 0.414 for anti-Xa (p < 0.001). Major thrombotic and hemorrhagic events occurred in 14.7% and 26.5% of patients, respectively. The median anti-Xa in patients who experienced a major thrombotic event was 0.09 (0.06-0.25) IU/mL compared with 0.36 (0.26-0.44) IU/mL in patients who did not (p = 0.031), whereas the median aPTT did not differ between these groups. The maximum aPTT in patients who experienced a major bleed was 96.9 (76.0-200) seconds compared with 63.5 (44.4-98.6) seconds in patients who did not (p = 0.049), whereas the maximum anti-Xa did not differ between these groups. Monitoring both anti-Xa and aPTT may be warranted to safely provide understanding of pure heparin activity as well as underlying bleeding diatheses in adult ECMO patients.

Background: There is a paucity of data evaluating optimal dosing strategies of commonly utilized opioids and sedatives for patients on extracorporeal membrane oxygenation (ECMO) support where pharmacokinetic and pharmacodynamic variables of these administered agents are altered. Objective: To assess the daily dosing requirement of sedatives and analgesics for patients on venovenous (VV) and venoarterial (VA) ECMO after the initial ECMO cannulation period. Methods: We performed a retrospective, observational study of adult patients receiving sedation and analgesia while receiving ECMO support for at least 24 hours. Patients cannulated at an outside hospital more than 24 hours before transfer, those with a history of intravenous drug use or acute alcohol withdrawal, or those who died within 48 hours of ECMO initiation were excluded. Results: We evaluated 26 patients on ECMO, including 13 on VV and 13 on VA ECMO. The median dose of fentanyl was 140 µg/h, with the VV group requiring a higher dose compared with the VA group (167 vs 106 µg/h, P < 0.001). The median doses of dexmedetomidine and propofol were 0.7 µg/kg/h and 26 µg/kg/min, respectively, with no significant differences between groups ( P = 0.38 and P = 0.24, respectively). The median daily doses of fentanyl, dexmedetomidine, and propofol did not significantly increase throughout the time on ECMO support. Conclusions and Relevance: We found that the overall opioid daily dosing requirements were lower than previously reported in the literature. Additionally, light sedation strategies with a target RASS of -1 to 0 are feasible in this patient population.

Breast cancer is the most common malignancy among reproductive-aged women, and an increasing number of women are breastfeeding at the time of screening initiation. The literature was reviewed to identify evidence-based guidelines for breast cancer screening during lactation. Health care providers should consider routine age-related or high-risk screening; they should also discuss alternate surveillance strategies, including deferment until cessation of breastfeeding. Shared decision-making and individualized patient care should involve consideration of the limitations of current evidence. Lactation-related radiographic changes may make examination interpretation more challenging; preprocedure milk expression and use of particular supplemental imaging modalities can improve examination sensitivity. Despite these strategies, breastfeeding women may have higher rates of false-positive findings and therefore undergo more biopsies. However, given the increased risk of biologically aggressive breast cancers in postpartum women, these risks may be outweighed by the benefits of routine breast cancer screening for breastfeeding women.

The American Thoracic Society Pediatric Core Curriculum updates clinicians annually in pediatric pulmonary disease in a 3 to 4 year recurring cycle of topics. The 2019 course was presented in May during the Annual International Conference. An American Board of Pediatrics Maintenance of Certification module and a continuing medical education exercise covering the contents of the Core Curriculum can be accessed online at www.thoracic.org., (© 2019 Wiley Periodicals, Inc.)

Venous thromboembolism (VTE) is a major health concern associated with significant morbidity and mortality. Critically ill patients are at an increased risk of VTE compared to general medical patients due to unique risk factors: prolonged immobilization, invasive lines and devices, certain medications, and acquired thrombophilia. Furthermore, VTE in the critically ill is associated with increased duration of mechanical ventilation, increased length of intensive care unit and hospital stay, and a trend toward increased mortality. Clinical practice guidelines therefore recommend VTE prophylaxis with either subcutaneous heparin or low-molecular-weight heparin for all critically ill patients without contraindication. Yet, many patients will develop VTE despite appropriate pharmacologic prophylaxis, which has led to interest in risk-stratifying critically ill patients for more aggressive prophylaxis strategies. Recent research identified patients at highest risk of failure of thromboprophylaxis and provided insight into the pathophysiologic mechanisms. Obesity and the receipt of vasopressors are 2 risk factors consistently identified in observational studies; further clinical data support decreased absorption of anticoagulant administered via the subcutaneous route as the likely mechanism behind thromboprophylaxis failure in these patient populations. Several studies have investigated novel thromboprophylaxis strategies to circumvent pharmacokinetic limitations in patients who are obese or on vasopressors: increased fixed-dose, weight-based subcutaneous, or continuous intravenous infusion of a prophylactic dose of anticoagulant has shown promise in limited studies; however, the results have yet to demonstrate superiority compared to current standard-of-care. This review discusses observational studies identifying patients at risk of thromboprophylaxis failure and critiques clinical studies evaluating novel thromboprophylaxis strategies in high-risk, critically ill patients with a focus on their limitations. Future studies are currently being conducted that will provide further guidance into the appropriate use of individualized thromboprophylaxis.

Activation of the inflammasome is a key function of the innate immune response that regulates inflammation in response to microbial substances. Inflammasome activation by human rhinovirus (RV), a major cause of asthma exacerbations, has not been well studied. We examined whether RV induces inflammasome activation in vivo, molecular mechanisms underlying RV-stimulated inflammasome priming and activation, and the contribution of inflammasome activation to RV-induced airway inflammation and exacerbation. RV infection triggered lung mRNA and protein expression of pro-IL-1β and NLRP3, indicative of inflammasome priming, as well as cleavage of caspase-1 and pro-IL-1β, completing inflammasome activation. Immunofluorescence staining showed IL-1β in lung macrophages. Depletion with clodronate liposomes and adoptive transfer experiments showed macrophages to be required and sufficient for RV-induced inflammasome activation. TLR2 was required for RV-induced inflammasome priming in vivo. UV irradiation blocked inflammasome activation and RV genome was sufficient for inflammasome activation in primed cells. Naive and house dust mite-treated NLRP3-/- and IL-1β-/- mice, as well as IL-1 receptor antagonist-treated mice, showed attenuated airway inflammation and responsiveness following RV infection. We conclude that RV-induced inflammasome activation is required for maximal airway inflammation and hyperresponsiveness in naive and allergic mice. The inflammasome represents a molecular target for RV-induced asthma exacerbations.

Inotropes are an integral component of the early stabilization of the patient presenting with cardiogenic shock. Despite years of clinical experience with the 2 most commonly used inotropes, dobutamine and milrinone, there remains limited data comparing outcomes between the two. We conducted a retrospective review to compare the effectiveness and safety of milrinone or dobutamine for the initial management of cardiogenic shock. Adult patients with cardiogenic shock regardless of etiology who received initial inotrope therapy with either milrinone (n = 50) or dobutamine (n = 50) and did not receive mechanical circulatory support were included. The primary end point was the time to resolution of cardiogenic shock. Changes in hemodynamic parameters from baseline and adverse events were also assessed. Resolution of shock was achieved in similar numbers in both the groups (milrinone 76% vs dobutamine 70%, P = .50). The median time to resolution of shock was 24 hours in both groups ( P = .75). There were no differences in hemodynamic changes during inotrope therapy, although dobutamine trended toward a greater increase in cardiac index. Arrhythmias were more common in patients treated with dobutamine than milrinone, respectively (62.9% vs 32.8%, P < .01), whereas hypotension occurred to a similar extent in both groups (milrinone 49.2% vs dobutamine 40.3%, P = .32). The use of concomitant vasoactive medications, dosage required, and duration of therapy did not differ between groups. There was no difference in the overall rate of discontinuation due to adverse event; however, milrinone was more commonly discontinued due to hypotension (13.1% vs 0%, P < .01) and dobutamine was more commonly discontinued due to arrhythmia (0% vs 11.3%, P < .01). Milrinone and dobutamine demonstrated similar effectiveness and safety profiles but with differences in adverse events. The choice of milrinone or dobutamine as initial inotrope therapy for cardiogenic shock may depend more on tolerability of adverse events.

Background: Upper respiratory tract viral infections cause asthma exacerbations in children. However, the impact of natural colds on children with asthma in the community, particularly in the high-risk urban environment, is less well defined., Objective: We hypothesized that children with high-symptom upper respiratory viral infections have reduced airway function and greater respiratory tract inflammation than children with virus-positive low-symptom illnesses or virus-negative upper respiratory tract symptoms., Methods: We studied 53 children with asthma from Detroit, Michigan, during scheduled surveillance periods and self-reported respiratory illnesses for 1 year. Symptom score, spirometry, fraction of exhaled nitric oxide (FeNO), and nasal aspirate biomarkers, and viral nucleic acid and rhinovirus (RV) copy number were assessed., Results: Of 658 aspirates collected, 22.9% of surveillance samples and 33.7% of respiratory illnesses were virus-positive. Compared with the virus-negative asymptomatic condition, children with severe colds (symptom score ≥5) showed reduced forced expiratory flow at 25% to 75% of the pulmonary volume (FEF 25%-75% ), higher nasal messenger RNA expression of C-X-C motif chemokine ligand (CXCL)-10 and melanoma differentiation-associated protein 5, and higher protein abundance of CXCL8, CXCL10 and C-C motif chemokine ligands (CCL)-2, CCL4, CCL20, and CCL24. Children with mild (symptom score, 1-4) and asymptomatic infections showed normal airway function and fewer biomarker elevations. Virus-negative cold-like illnesses demonstrated increased FeNO, minimal biomarker elevation, and normal airflow. The RV copy number was associated with nasal chemokine levels but not symptom score., Conclusion: Urban children with asthma with high-symptom respiratory viral infections have reduced FEF 25%-75% and more elevations of nasal biomarkers than children with mild or symptomatic infections, or virus-negative illnesses., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Few longitudinal studies examine inflammation and lung function in asthma. We sought to determine the cytokines that reduce airflow, and the influence of respiratory viral infections on these relationships., Methods: Children underwent home collections of nasal lavage during scheduled surveillance periods and self-reported respiratory illnesses. We studied 53 children for one year, analyzing 392 surveillance samples and 203 samples from 85 respiratory illnesses. Generalized estimated equations were used to evaluate associations between nasal lavage biomarkers (7 mRNAs, 10 proteins), lung function and viral infection., Results: As anticipated, viral infection was associated with increased cytokines and reduced FVC and FEV 1 . However, we found frequent and strong interactions between biomarkers and virus on lung function. For example, in the absence of viral infection, CXCL10 mRNA, MDA5 mRNA, CXCL10, IL-4, IL-13, CCL4, CCL5, CCL20 and CCL24 were negatively associated with FVC. In contrast, during infection, the opposite relationship was frequently found, with IL-4, IL-13, CCL5, CCL20 and CCL24 levels associated with less severe reductions in both FVC and FEV 1 ., Conclusions: In asthmatic children, airflow obstruction is driven by specific pro-inflammatory cytokines. In the absence of viral infection, higher cytokine levels are associated with decreasing lung function. However, with infection, there is a reversal in this relationship, with cytokine abundance associated with reduced lung function decline. While nasal samples may not reflect lower airway responses, these data suggest that some aspects of the inflammatory response may be protective against viral infection. This study may have ramifications for the treatment of viral-induced asthma exacerbations.

Contrast-enhanced digital mammography (CEDM) is the only imaging modality that provides both (a) a high-resolution, low-energy image comparable to that of digital mammography and (b) a contrast-enhanced image similar to that of magnetic resonance imaging. We report the initial 208 CEDM examinations performed for various clinical indications and provide illustrative case examples. Given its success in recent studies and our experience of CEDM primarily as a diagnostic adjunct, CEDM can potentially improve breast cancer detection by combining the low-cost conclusions of screening mammography with the high sensitivity of magnetic resonance imaging., (© 2016 Wiley Periodicals, Inc.)

Since W. E. B. Du Bois documented the physical and social environments of Philadelphia's predominantly African American Seventh Ward over a century ago, there has been continued interest in understanding the distribution of social and physical environments by racial make-up of communities. Characterization of these environments allows for documentation of inequities, identifies communities which encounter heightened risk, and can inform action to promote health equity. In this paper, we apply and extend Du Bois's approach to examine the contemporary distribution of physical environmental exposures, health risks, and social vulnerabilities in the Detroit metropolitan area, one of the most racially-segregated areas in the United States. We begin by mapping the proximity of sensitive populations to hazardous land uses, their exposure to air pollutants and associated health risks, and social vulnerabilities, as well as cumulative risk (combined proximity, exposure, and vulnerability), across Census tracts. Next, we assess, quantitatively, the extent to which communities of color experience excess burdens of environmental exposures and associated health risks, economic and age-related vulnerabilities, and cumulative risk. The results, depicted in maps presented in the paper, suggest that Census tracts with greater proportions of people of color disproportionately encounter physical environmental exposures, socioeconomic vulnerabilities, and combined risk. Quantitative tests of inequality confirm these distributions, with statistically greater exposures, vulnerabilities, and cumulative risk in Census tracts with larger proportions of people of color. Together, these findings identify communities that experience disproportionate cumulative risk in the Detroit metropolitan area and quantify the inequitable distribution of risk by Census tract relative to the proportion of people of color. They identify clear opportunities for prioritizing communities for legislative, regulatory, policy, and local actions to promote environmental justice and health equity.

Rationale: The mechanism by which viruses cause exacerbations of chronic airway disease and the capacity of patients with cystic fibrosis (CF) to respond to viral infection are not precisely known., Objectives: To determine the antiviral response to infection in patients with CF., Methods: Sputum was collected from patients with CF with respiratory exacerbation. Viruses were detected in multiplex polymerase chain reaction (PCR)-based assays. Gene expression of 84 antiviral response genes was measured, using a focused quantitative PCR gene array., Measurements and Main Results: We examined 36 samples from 23 patients with respiratory exacerbation. Fourteen samples tested virus-positive and 22 virus-negative. When we compared exacerbations associated with rhinovirus (RV, n = 9) and influenza (n = 5) with virus-negative specimens, we found distinct patterns of antiviral gene expression. RV was associated with greater than twofold induction of five genes, including those encoding the monocyte-attracting chemokines CXCL10, CXCL11, and CXCL9. Influenza was associated with overexpression of 20 genes, including those encoding the cytokines tumor necrosis factor and IL-12; the kinases MEK, TBK-1, and STAT-1; the apoptosis proteins caspase-8 and caspase-10; the influenza double-stranded RNA receptor RIG-I and its downstream effector MAVS; and pyrin, an IFN-stimulated protein involved in influenza resistance., Conclusions: We conclude that virus-induced exacerbations of CF are associated with immune responses tailored to specific infections. Influenza induced a more potent response consisting of inflammation, whereas RV infection had a pronounced effect on chemokine expression. As far as we are aware, this study is the first to compare specific responses to different viruses in live patients with chronic airway disease.

Immediate early genes (IEGs) are expressed upon re-entry of quiescent cells into the cell cycle following serum stimulation. These genes are involved in growth control and differentiation and hence their expression is tightly controlled. Many IEGs are regulated through Serum Response Elements (SREs) in their promoters, which bind Serum Response Factor (SRF). However, many other IEGs do not have SREs in their promoters and their serum regulation is poorly understood. We have identified SRF-independent IEGs in SRF-depleted fibroblasts. One of these, Id1, was examined more closely. We mapped a serum responsive element in the Id1 promoter and find that it is identical to a BMP responsive element (BRE). The Id1 BRE is necessary and sufficient for the serum regulation of Id1. Inhibition of the BMP pathway by siRNA depletion of Smad 4, treatment with the BMP antagonist noggin, or the BMP receptor inhibitor dorsomorphin blocked serum induction of Id1. Further, BMP2 is sufficient to induce Id1 expression. Given reports that SRC inhibitors can block Id1 expression, we tested the SRC inhibitor, AZD0530, and found that it inhibits the serum activation of Id1. Surprisingly, this inhibition is independent of SRC or its family members. Rather, we show that AZD0530 directly inhibits the BMP type I receptors. Serum induction of the Id1 related gene Id3 also required the BMP pathway. Given these and other findings we conclude that the Id family of IEGs is regulated by BMPs in serum through similar BREs. This represents a second pathway for serum regulation of IEGs., (© 2013 Elsevier B.V. All rights reserved.)

Caregiving for ill loved ones can affect sleep quality and quantity. Insufficient sleep has been associated with worse physical and mental health outcomes, and it is known to affect work performance and ability to accomplish necessary tasks. While some research has looked at the sleep of caregivers of loved ones with chronic illness and found that they experience poorer sleep, little is known about the impact of caring for a child with asthma on the caregiver's sleep and the ways in which their sleep may be affected. Community Action Against Asthma, a community-based participatory research partnership, conducted interviews with semistructured and open-ended questions with 40 caregivers of children with asthma who live in Detroit. Findings showed that caregivers regularly experience poor quality sleep because of sleeping lightly in order to listen for the child's symptoms, wake multiple times to check on the child because of worry, and provide care for child when he or she experiences symptoms in the middle of the night. Results of the Epworth Sleepiness Scale indicate that 12.5% of caregivers received a score of 16 or more, the score on the scale used to indicate likely presence of a sleep disorder, and 42.5% had a score of 10 or more, indicating excessive sleepiness. Sleep disturbance in caregivers is an underrecognized consequence of childhood asthma, with implications for providers caring for children with asthma.

Rationale: Information on how ambient air pollution affects susceptible populations is needed to ensure protective air quality standards., Objectives: To estimate the effect of community-level ambient particulate matter (PM) and ozone (O) on respiratory symptoms among primarily African-American and Latino, lower-income asthmatic children living in Detroit, Michigan and to evaluate factors associated with heterogeneity in observed health effects., Methods: A cohort of 298 children with asthma was studied prospectively from 1999 to 2002. For 14days each season over 11 seasons, children completed a respiratory symptom diary. Simultaneously, ambient pollutant concentrations were measured at two community-level monitoring sites. Logistic regression models using generalized estimating equations were fit for each respiratory symptom in single pollutant models, looking for interactions by area or by corticosteroid use, a marker of more severe asthma. Exposures of interest were: daily concentrations of PM<10μm, <2.5μm, and between 10 and 2.5μm in aerodynamic diameter (PM, PM, and PM respectively), the daily 8-hour maximum concentration of O (8HrPeak), and the daily 1-hour maximum concentration of O (1HrPeak)., Results: Outdoor PM, PM, 8HrPeak, and 1HrPeak O concentrations were associated with increased odds of respiratory symptoms, particularly among children using corticosteroid medication and among children living in the southwest community of Detroit. Similar patterns of associations were not seen with PM., Conclusions: PM and O at levels near or below annual standard levels are associated with negative health impact in this population of asthmatic children. Variation in effects within the city of Detroit and among the subgroup using steroids emphasizes the importance of spatially refined exposure assessment and the need for further studies to elucidate mechanisms and effective risk reduction interventions., (Copyright © 2012. Published by Elsevier B.V.)

Low-income caregivers of children with asthma experience multiple stressors, likely worsening family health. As part of Community Action Against Asthma's community-based participatory research partnership, researchers conducted 40 qualitative semi-structured interviews and quantitative surveys with low-income caregivers of children with asthma in Detroit, Michigan. Participants described daily childhood asthma experiences and completed scales including the Peds Quality of Life Family Impact Module and Zarit Burden Caregiver Scale. Quantitative scale findings suggested participants are moderately stressed or affected by their child's illness. While there was some accordance between qualitative and quantitative findings, qualitative findings additionally captured many relevant life stressors, seemingly overlooked or conflated in scale responses. Many participants described asthma as part of childrearing, rather than as a stressor or burden. Findings encourage improvement of clinical, psychometric assessments used to measure and address stressors that shape health for many families with children with asthma.

Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1β, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.

The Alabama Coalition for a Healthier Black was a demonstration of concept project. This paper is a descriptive and qualitative overview of this 2.5 year project. Limited key project results are reported here. Located in the rural Black Belt region of Alabama this coalition had several key aims: to develop a collaboration between primary care and mental health care through co-location of services; use of video-conferencing capability to provide mental health services more efficiently; enhanced training in rural healthcare; and development of stigma reduction campaigns along with other coalition partner specific initiatives. Co-location and telepsychiatry implementation produced the major challenges and resulting adaptations to original aims. Despite many challenges these new service patterns were put into place and appear to be sustainable.

Background: The mechanisms by which viruses induce asthma exacerbations are not well understood., Objective: We characterized fluctuations in nasal aspirate cytokines during naturally occurring respiratory viral infections in children with asthma., Methods: Sixteen children underwent home collections of nasal aspirates when they were without cold symptoms and again during self-reported respiratory illnesses. The presence of viral infection was ascertained by multiplex PCR. Cytokines were measured using multiplex immune assay. mRNA expression for selected markers of viral infection was measured using RT-PCR. A cumulative respiratory symptom score was calculated for each day of measurement. Generalized estimated equations were used to evaluate associations between viral infection and marker elevation, and between marker elevation and symptom score., Results: The 16 patients completed a total of 37 weeks of assessment (15 'well' weeks; 22 self-assessed 'sick' weeks). Viral infections were detected in 3 of the 'well' weeks and 17 of the 'sick' weeks (10 rhinovirus, three coronavirus, two influenza A, two influenza B, two respiratory syncytial virus, one parainfluenza). Compared to virus-negative well weeks, nasal aspirate IFN-γ, CXCL8/IL-8, CXCL10/IP-10, CCL5/RANTES, CCL11/eotaxin-1, CCL2/MCP-1, CCL4/MIP-1β, CCL7/MCP-3, and CCL20/MIP3α protein levels increased during virus-positive sick weeks. Only a subset of cytokines (IFN-γ, CXCL8, CCL2, CCL4, CCL5, and CCL20) correlated with self-reported respiratory tract symptoms. While many aspirates were dilute and showed no mRNA signal, viral infection significantly increased the number of samples that were positive for IFN-λ1, IFN-λ2/3, TLR3, RIG-I, and IRF7 mRNA., Conclusions and Clinical Relevance: We conclude that in children with asthma, naturally occurring viral infections apparently induce a robust innate immune response including expression of specific chemokines, IFNs, and IFN-responsive genes., (© 2012 Blackwell Publishing Ltd.)

A bis-quinoline compound, (7-chloro-N-(4-(7-chloroquinolin-4-ylamino)butyl)quinolin-4-amine; RE-660) was found to have C-C chemokine receptor type 1 (CCR1)-agonistic properties. RE-660 displayed strong adjuvantic activity in mice when co-administered with bovine α-lactalbumin used as a model subunit protein antigen. RE-660 evoked a balanced Th1 (IgG2)/Th2 (IgG1) antibody profile, and the quality of antibodies elicited by the bis-quinoline was found to be superior to that evoked by glucopyranosyl lipid A by surface plasmon resonance experiments. No evidence of proinflammatory activity was observed in human blood ex vivo models. In preliminary acute toxicity studies, the compound was found to be of lower toxicity than chloroquine in mice, and was non-mutagenic in an Ames screen., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM(2)CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C(16)) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.

Toll-like receptor (TLR)-7 agonists show prominent Th1-biased immunostimulatory activities. A TLR7-active N(1)-(4-aminomethyl)benzyl substituted imidazoquinoline 1 served as a convenient precursor for the syntheses of isothiocyanate and maleimide derivatives for covalent attachment to free amine and thiol groups of peptides and proteins. 1 was also amenable to direct reductive amination with maltoheptaose without significant loss of activity. Covalent conjugation of the isothiocyanate derivative 2 to α-lactalbumin could be achieved under mild, non-denaturing conditions, in a controlled manner and with full preservation of antigenicity. The self-adjuvanting α-lactalbumin construct induced robust, high-affinity immunoglobulin titers in murine models. The premise of covalently decorating protein antigens with adjuvants offers the possibility of drastically reducing systemic exposure of the adjuvant, and yet eliciting strong, Th1-biased immune responses., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: To determine whether short-acting beta-agonist (SABA) prescriber continuity was associated with emergency department visits among children with asthma., Study Design: An analysis of Michigan Medicaid administrative claims (2004-2005) for children ages 5 to 18 with asthma. Logistic regression models assessed the effect of SABA prescriber continuity (the number and site of prescribers) on emergency department visits, controlling for demographics, historical (2004) asthma use and SABA prescription frequency (2-5 low; > or = 6 high)., Results: Most children had one SABA prescriber (62%); 13% had multiple prescribers in the same practice as the primary care provider and 25% had multiple prescribers in different practices. Children with multiple prescribers in different practices had increased odds of an emergency department visit compared with those with 1 prescriber, among those with high SABA prescription frequency (AOR: 2.7, 95% CI: 1.9, 3.9), as well as those with low prescription frequency (AOR: 1.7, 95% CI: 1.3, 2.2)., Conclusions: Children with discontinuity of SABA prescribers have an increased risk of asthma emergency department visits, irrespective of their SABA prescription frequency. Primary care providers may have difficulty identifying patients at high risk with asthma solely on the basis of SABAs prescribed within their own practices.

Background: Longstanding recommendations for influenza vaccines among children were augmented by the Advisory Committee on Immunization Practices (ACIP) in 2002 and again in 2008 to encourage vaccination among healthy children aged 6 months-18 years. Little is known about the hospital costs and length of stay among high-risk and otherwise healthy children for the groups affected by the 2002 and 2008 recommendations of the ACIP. The burden of influenza may vary between children with high-risk medical conditions and those who are otherwise healthy. The objective of the current study was to characterize the national burden of influenza hospitalizations and to evaluate how hospital costs and length of stay varied among children diagnosed with influenza., Methods: A retrospective analysis of influenza hospitalizations was performed in 2006 using the Healthcare Cost and Utilization Project Kids' Inpatient Database, a nationally representative database of hospital discharge records for children from January to December 2003. Children aged