Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

INTRODUCTION: Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. METHODS: Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. RESULTS: There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. CONCLUSION: This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

A very complicated UTI: malakoplakia following E. coli urinary tract infection.

Malakoplakia is a rare inflammatory disorder believed to result from a defect in macrophage phagocytic function triggering a granulomatous reaction. It can present with genitourinary, gastrointestinal, or cutaneous manifestations in immunocompromised or, less commonly, immunocompetent hosts. We describe a case of renal malakoplakia in a young, otherwise healthy patient presenting with nephromegaly and sepsis following an E. coli urinary tract infection. We discuss diagnosis and management, including antibiotic selection and the decision to pursue nephrectomy. This case highlights the potential for kidney recovery with prolonged antibiotic therapy in conjunction with adjunct immunomodulatory therapies and source control.

Heterogeneous trajectories of suicidal ideation among homeless youth: predictors and suicide-related outcomes.

The current study examined heterogeneous trajectories of suicidal ideation among homeless youth experiencing suicidal ideation over 9 months in a randomized controlled intervention study. Suicidal homeless youth (N = 150) were randomly assigned to Cognitive Therapy for Suicide Prevention (CTSP) + Treatment as Usual (TAU) or TAU alone. Youth reported their suicidal ideation four times during a 9-month period. We also assessed pretreatment mental health, demographic information and session attendance as predictors of the subgroups, as well as suicide-related factors as outcomes at the 9-month follow-up. Growth mixture models suggested three distinct trajectory groups among youth: Fast Declining (74.7%), Chronic (19.3%), and Steadily Declining (6.0%). Youth in the Chronic group used more substances at baseline than the Steadily Declining group, were more likely to be White, non-Hispanic than the Fast Declining group, and attended more CTSP sessions than other groups. Contrastingly, youth in the Steadily Declining group all experienced childhood abuse. Finally, youth in the Chronic group showed significant higher risk for future suicide compared to those in the Fast Declining group at 9 months. Findings support the heterogeneity of treatment responses in suicide intervention among homeless youth, with implications to improve treatment efforts in this very high-risk population.

Timing of cesarean delivery in women with ≥2 previous cesarean deliveries.

BACKGROUND: The rate of cesarean delivery is continuously increasing with the leading indication being a previous cesarean delivery. For women with 1 previous cesarean delivery, it is generally agreed that the optimal timing of delivery by elective cesarean delivery is during the 39th week of gestation, whereas for women with ≥2 previous cesarean deliveries, the optimal delivery time remains debatable. OBJECTIVE: To assess the maternal and neonatal risks associated with elective delivery at different gestational ages ranging from 37 0/7 to 39 6/7 weeks' gestation and to compare it with expectant management among women with at least 2 previous cesarean deliveries. STUDY DESIGN: This was a retrospective, population-based cohort study of all women with at least 2 previous cesarean deliveries who delivered after 36 6/7 weeks of gestation in Ontario, Canada, between April 2012 and March 2019. Women with multifetal pregnancies or major fetal anomalies were excluded. For each completed gestational week, outcomes of women who had an elective repeat cesarean delivery at that week solely because of 2 previous cesarean deliveries were compared with the outcomes of those who were managed expectantly and delivered at a later gestational age. The primary outcome was a composite of maternal outcomes including mortality and severe maternal morbidity. Secondary outcomes were adverse neonatal outcomes. RESULTS: A total of 26,522 women met the inclusion criteria. The maternal risk was similar for elective delivery at 37 0/7 to 38 6/7 weeks of gestation compared with expectant management. However, elective delivery at 39 0/7 to 39 6/7 weeks' gestation was associated with a decreased risk for adverse outcomes when compared with expectant management (adjusted risk ratio, 0.51; 95% confidence interval, 0.29-0.91). For the neonate, elective delivery during the 37th week of gestation significantly increased the incidence of the composite adverse outcome than in an ongoing pregnancy (adjusted risk ratio, 1.68; 95% confidence interval, 1.39-2.01), but was comparable for elective delivery at 38 0/7 to 39 6/7 weeks' gestation and expectant management. The risk for an unplanned cesarean delivery increased from 6.5% before 38 weeks' gestation to 21.7% before 39 weeks' gestation and to 32.6% before 40 weeks' gestation. CONCLUSION: For women with ≥2 cesarean deliveries, elective delivery at 38 0/7 to 38 6/7 weeks' gestation likely represents the optimal balance between neonatal and maternal risk while decreasing the likelihood of an unplanned cesarean delivery.

Environmental influences on childhood asthma-The effect of diet and microbiome on asthma.

Early life dietary patterns and timely maturation of mucosa-associated microbial communities are important factors influencing immune development and for establishing robust immune tolerance networks. Microbial fermentation of dietary components in vivo generates a vast array of molecules, some of which are integral components of the molecular circuitry that regulates immune and metabolic functions. These in turn protect against aberrant inflammatory processes and promote effector immune responses that quickly eliminate pathogens. Multiple studies suggest that changes in dietary habits, altered microbiome composition, and microbial metabolism are associated with asthma risk and disease severity. While it remains unclear whether these microbiome alterations are a cause or consequence of dysregulated immune responses, there is significant potential for using diet in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health. In this article, we will summarize our knowledge to date on the role of dietary patterns and microbiome activities on immune responses within the airways. Given the malleability of the human microbiome, its integration into the immune system, and its responsiveness to diet, this makes it a highly attractive target for therapeutic and nutritional intervention in children with asthma.

Endobronchial Balloon Blockers: A Retrospective Analysis of Their Implementation for Use in Transbronchial Cryobiopsy Under Conscious Sedation.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is a promising technique that is evolving as a standard diagnostic procedure in the diagnosis of interstitial lung disease. However, there are a variety of non-standardised techniques adopted for this procedure. We aim to describe our approach to TBLC with balloon blockade under conscious sedation (CS). METHODS: We performed a retrospective analysis of patients undergoing TBLC using flexible bronchoscopy under CS in our institution over the calendar years 2017-2018; before and after a transition to the use of endobronchial balloon blockers (EBB) in 2017. RESULTS: 25 patients underwent transbronchial cryobiopsy during the study period. Of these; 12 procedures used EBB. EBB subjects had significantly less moderate or severe airway bleeding (8.3% vs 38.5%) despite higher biopsy rates in the EBB group, 2.9 (2-4) vs 2.4 (1-4) in the non-EBB group. No severe airway bleeding occurred in the EBB group. A multidisciplinary meeting (MDM) confirmed diagnosis was achieved in 88% of patients. 10/12 subjects (83%) in the EBB group and 12/13 subjects (92%) in the non-EBB group (p = 0.5). CONCLUSION: Our institution is novel in using EBB as standard during TBLC specifically under CS with flexible bronchoscopy in the bronchoscopy suite. This retrospective analysis demonstrates that EBB enhances the safety profile of performing TBLC under CS and did not appear to impact diagnostic yield or patient safety.

Housing First Combined with Suicide Treatment Education and Prevention (HOME + STEP): study protocol for a randomized controlled trial.

BACKGROUND: Youth experiencing homelessness are at high risk for suicide, yet few studies have evaluated risk reduction interventions targeting suicidal ideation in this vulnerable population. A comprehensive approach to risk-reduction is needed that addresses basic needs and provides targeted interventions for those at highest risk. The protocol described builds on the design of the first randomized trial of Housing First (HF) for homeless youth. The primary objective is to determine whether housing combined with supportive services that include suicide screening and targeted psychotherapy (Cognitive Therapy for Suicide Prevention) is effective for reducing suicidal ideation and other secondary outcomes (depression and suicide attempts). Additionally, we will explore mediators of the treatment effect (housing stability and substance use) and determinants of implementation. METHODS: Youth recruited to the HF trial will be randomized to HF + supportive services (n = 120), or supportive services alone (n = 120). The "Suicide Treatment Education and Prevention" (STEP) protocol will additionally screen youth in both arms at baseline and 3 months for suicidal ideation (SSI-W). Those who screen as moderate risk for suicide (SSI-W ≥ 10) will be offered CTSP, which includes up to 9 sessions over the first 6 months following enrollment. CTSP will be delivered in one-on-one sessions by a trained advocate. Research assessments will be collected to assess outcomes (including suicidal ideation) at baseline, 3, 6, 9 and 12 months. Qualitative interviews with subjects receiving CTSP and other stakeholders will explore implementation determinants. DISCUSSION: The study will fill an important gap in the literature about the added benefit of HF combined with supportive services including suicide screening and treatment for reducing suicidal ideation in homeless youth. With the urgent need to address both homelessness and suicide risk, evidence is needed about services that can be integrated into delivery settings for youth experiencing homelessness. TRIAL REGISTRATION: NCT04135703 . Date of registration: October 23, 2019.

Association of Maternal Influenza Vaccination During Pregnancy With Early Childhood Health Outcomes.

Importance: Seasonal influenza vaccination in pregnancy can reduce influenza illness among pregnant women and newborns. Evidence is limited on whether seasonal influenza vaccination in pregnancy is associated with adverse childhood health outcomes. Objective: To assess the association between maternal influenza vaccination during pregnancy and early childhood health outcomes. Design, Setting, and Participants: Retrospective cohort study, using a birth registry linked with health administrative data. All live births in Nova Scotia, Canada, between October 1, 2010, and March 31, 2014, were included, with follow-up until March 31, 2016. Adjusted hazard ratios (HRs) and incidence rate ratios (IRRs) with 95% confidence intervals were estimated while controlling for maternal medical history and other potential confounders using inverse probability of treatment weighting. Exposures: Seasonal influenza vaccination during pregnancy. Main Outcomes and Measures: Childhood outcomes studied were immune-related (eg, asthma, infections), non-immune-related (eg, neoplasms, sensory impairment), and nonspecific (eg, urgent or inpatient health care utilization), measured from emergency department and hospitalization databases. Results: Among 28 255 children (49% female, 92% born at ≥37 weeks' gestation), 10 227 (36.2%) were born to women who received seasonal influenza vaccination during pregnancy. During a mean follow-up of 3.6 years, there was no significant association between maternal influenza vaccination and childhood asthma (incidence rate, 3.0 vs 2.5 per 1000 person-years; difference, 0.53 per 1000 person-years [95% CI, -0.15 to 1.21]; adjusted HR, 1.22 [95% CI, 0.94 to 1.59]), neoplasms (0.32 vs 0.26 per 1000 person-years; difference, 0.06 per 1000 person-years [95% CI, -0.16 to 0.28]; adjusted HR, 1.26 [95% CI, 0.57 to 2.78]), or sensory impairment (0.80 vs 0.97 per 1000 person-years; difference, -0.17 per 1000 person-years [95% CI, -0.54 to 0.21]; adjusted HR, 0.82 [95% CI, 0.49 to 1.37]). Maternal influenza vaccination in pregnancy was not significantly associated with infections in early childhood (incidence rate, 184.6 vs 179.1 per 1000 person-years; difference, 5.44 per 1000 person-years [95% CI, 0.01 to 10.9]; adjusted IRR, 1.07 [95% CI, 0.99 to 1.15]) or with urgent and inpatient health services utilization (511.7 vs 477.8 per 1000 person-years; difference, 33.9 per 1000 person-years [95% CI, 24.9 to 42.9]; adjusted IRR, 1.05 [95% CI, 0.99 to 1.16]). Conclusions and Relevance: In this population-based cohort study with mean follow-up duration of 3.6 years, maternal influenza vaccination during pregnancy was not significantly associated with an increased risk of adverse early childhood health outcomes.

Youth Experiencing Homelessness with Suicidal Ideation: Understanding Risk Associated with Peer and Family Social Networks.

Suicide is the leading cause of death among youth experiencing homelessness, and these youth report high rates of suicide attempts. Research suggests that the interpersonal factors of perceived burdensomeness and thwarted belongingness are proximal causes of suicide, but little is known about factors associated with these risks. The current study examined the relationship of social network characteristics, perceived social network support, and interpersonal risks for suicide among a sample of 150 youth experiencing homelessness who reported severe suicide ideation. Findings indicate that characteristics of the social network, including engagement in crime and alcohol use, interrupted the potentially protective effects of high perceived social network support for interpersonal risk factors of suicide. Findings imply that increasing perceived social network support as a protection against suicide will not be uniformly successful, and consideration of the social network characteristics is necessary. Future work needs to continue to uncover the complexity of modifiable intervention targets to prevent future suicide attempts among this high-risk group.

Predictors of Treatment Engagement Among Suicidal Youth Experiencing Homelessness.

Homeless youth experience high rates of suicidal ideation and attempts, yet limited research has examined predictors of treatment engagement among this population. Suicidal homeless youth (N = 150) between the ages of 18 and 24 years were recruited from a drop-in center in Columbus, Ohio. Participants were randomly assigned to Cognitive Therapy for Suicide Prevention + treatment as usual through a local drop-in center (CTSP + TAU) (N = 75) or TAU alone (N = 75), and treatment attendance among those assigned to CTSP + TAU was examined in this study. As expected, among youth engaged in CTSP + TAU, those with a history of intimate partner violence (IPV) showed decreased odds of treatment attendance. Additionally, youth randomized into CTSP + TAU with higher acquired capability for suicide (ACS) scores and those identifying as Black were more likely to attend treatment sessions. Findings suggest that effective treatment implementation must consider youth's trauma history, demographics and severity of suicidal ideation and behaviors.

Use of non-invasive ventilation in motor neuron disease - a retrospective cohort analysis.

Motor neuron disease (MND) is a neurodegenerative disorder which leads to progressive muscle weakness including respiratory muscle decline. The introduction of non-invasive ventilation (NIV) has been shown to improve quality of life, survival and slow the rate of pulmonary function decline. A retrospective chart analysis of patients who attended the MND clinic from 2014 to 2019 at a tertiary-referral, academic, teaching hospital was carried out to evaluate if NIV and greater compliance with NIV was associated with improved survival. 111 patients were included. The mean age at diagnosis was 63.8 years and 61.3% were males. 66.7% of our cohort used NIV and of this 66.7%, 44.1% were compliant. There was a significantly longer survival in those who used NIV (p = 0.002) and in those who used NIV optimally (p = 0.02) when both groups were compared to those who did not use NIV. In the bulbar MND group those who were compliant with NIV survived longer than who those who did not use NIV (p = 0.001). We found a significantly longer survival with the use of NIV, the use of NIV optimally and with use of NIV in those with bulbar onset MND compared to those who did not use NIV.

Substance Use, Self-Efficacy, and Differentiation as Predictors of Intimate Partner Violence among Substance-Using Women.

Purpose: Intimate partner violence (IPV) is prevalent in the U.S., and has many physical and mental health implications. While several studies have explored the impact of IPV experience on individuals, less is known about which factors are predictive of IPV victimization. Method: The current study examined the extent to which substance use, self-efficacy, and differentiation each predicted experiences of IPV among women seeking treatment for a substance use disorder using a multinomial logistic regression analysis. Results: Results showed that women who reported lower levels of differentiation were significantly more likely to experience IPV. However, no other significant IPV predictors were found. Conclusions: Current findings suggest that differentiation may be an effective therapeutic target for IPV prevention.

Association Between Self-reported Prenatal Cannabis Use and Maternal, Perinatal, and Neonatal Outcomes.

Importance: Recent evidence suggests that cannabis use during pregnancy is increasing, although population-based data about perinatal outcomes following in utero exposure remain limited. Objective: To assess whether there are associations between self-reported prenatal cannabis use and adverse maternal and perinatal outcomes. Design, Setting, and Participants: Population-based retrospective cohort study covering live births and stillbirths among women aged 15 years and older in Ontario, Canada, between April 2012 and December 2017. Exposures: Self-reported cannabis exposure in pregnancy was ascertained through routine perinatal care. Main Outcomes and Measures: The primary outcome was preterm birth before 37 weeks' gestation. Indicators were defined for birth occurring at 34 to 36 6/7 weeks' gestation (late preterm), 32 to 33 6/7 weeks' gestation, 28 to 31 6/7 weeks' gestation, and less than 28 weeks' gestation (very preterm birth). Ten secondary outcomes were examined including small for gestational age, placental abruption, transfer to neonatal intensive care, and 5-minute Apgar score. Coarsened exact matching techniques and Poisson regression models were used to estimate the risk difference (RD) and relative risk (RR) of outcomes associated with cannabis exposure and control for confounding. Results: In a cohort of 661 617 women, the mean gestational age was 39.3 weeks and 51% of infants were male. Mothers had a mean age of 30.4 years and 9427 (1.4%) reported cannabis use during pregnancy. Imbalance in measured maternal obstetrical and sociodemographic characteristics between reported cannabis users and nonusers was attenuated using matching, yielding a sample of 5639 reported users and 92 873 nonusers. The crude rate of preterm birth less than 37 weeks' gestation was 6.1% among women who did not report cannabis use and 12.0% among those reporting use in the unmatched cohort (RD, 5.88% [95% CI, 5.22%-6.54%]). In the matched cohort, reported cannabis exposure was significantly associated with an RD of 2.98% (95% CI, 2.63%-3.34%) and an RR of 1.41 (95% CI, 1.36-1.47) for preterm birth. Compared with no reported use, cannabis exposure was significantly associated with greater frequency of small for gestational age (third percentile, 6.1% vs 4.0%; RR, 1.53 [95% CI, 1.45-1.61]), placental abruption (1.6% vs 0.9%; RR, 1.72 [95% CI, 1.54-1.92]), transfer to neonatal intensive care (19.3% vs 13.8%; RR, 1.40 [95% CI, 1.36-1.44]), and 5-minute Apgar score less than 4 (1.1% vs 0.9%; RR, 1.28 [95% CI, 1.13-1.45]). Conclusions and Relevance: Among pregnant women in Ontario, Canada, reported cannabis use was significantly associated with an increased risk of preterm birth. Findings may be limited by residual confounding.

Unprecedented widespread occurrence of Pink Salmon Oncorhynchus gorbuscha in Ireland in 2017.

The occurrence of non-native pink salmon Oncorhynchus gorbuscha in multiple river systems in Ireland in 2017 was unprecedented and reflected similar concurrent events observed in other countries in the North Atlantic region. Thirty-six fish were captured in a total of 11 river systems located in the south-west, west and north-west of Ireland in the period June to September 2017. The biological characteristics of sampled specimens are described and the potential for establishment in Ireland are considered.

Pilot Study Comparing Closed Versus Open Tracheal Suctioning in Postoperative Neonates and Infants With Complex Congenital Heart Disease.

OBJECTIVES: To determine the hemodynamic effect of tracheal suction method in the first 36 hours after high-risk infant heart surgery on the PICU and to compare open and closed suctioning techniques. DESIGN: Pilot randomized crossover study. SETTING: Single PICU in United Kingdom. PARTICIPANTS: Infants undergoing surgical palliation with Norwood Sano, modified Blalock-Taussig shunt, or pulmonary artery banding in the first 36 hours postoperatively. INTERVENTIONS: Infants were randomized to receive open or closed (in-line) tracheal suctioning either for their first or second study tracheal suction in the first 36 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: Twenty-four infants were enrolled over 18 months, 11 after modified Blalock-Taussig shunt, seven after Norwood Sano, and six after pulmonary artery banding. Thirteen patients received the open suction method first followed by the closed suction method second, and 11 patients received the closed suction method first followed by the open suction method second in the first 36 hours after their surgery. There were statistically significant larger changes in heart rate (p = 0.002), systolic blood pressure (p = 0.022), diastolic blood pressure (p = 0.009), mean blood pressure (p = 0.007), and arterial saturation (p = 0.040) using the open suction method, compared with closed suctioning, although none were clinically significant (defined as requiring any intervention). CONCLUSIONS: There were no clinically significant differences between closed and open tracheal suction methods; however, there were statistically significant greater changes in some hemodynamic variables with open tracheal suctioning, suggesting that closed technique may be safer in children with more precarious physiology.

Nanotopography facilitates in vivo transdermal delivery of high molecular weight therapeutics through an integrin-dependent mechanism.

Transdermal delivery of therapeutics is restricted by narrow limitations on size and hydrophobicity. Nanotopography has been shown to significantly enhance high molecular weight paracellular transport in vitro. Herein, we demonstrate for the first time that nanotopography applied to microneedles significantly enhances transdermal delivery of etanercept, a 150 kD therapeutic, in both rats and rabbits. We further show that this effect is mediated by remodeling of the tight junction proteins initiated via integrin binding to the nanotopography, followed by phosphorylation of myosin light chain (MLC) and activation of the actomyosin complex, which in turn increase paracellular permeability.

Women's sun protection cognitions in response to UV photography: the role of age, cognition, and affect.

This study examined the impact of ultraviolet (UV) photography, cognition versus affect, and age on women's sun-related cognitions and a proxy measure of sun protection behavior. Participants (N = 114) were recruited via public advertisements and came to the lab to view a photo showing their UV damage. In addition, some participants received instructions to focus on either their thoughts (cognition) or feelings (affect) about their photograph before completing the survey. Women in the affect condition reported the lowest perceived vulnerability to skin cancer and highest absent/exempt beliefs (beliefs that one is unlikely to develop skin cancer if she hasn't already). Condition by age interactions showed that, among those in the cognition and control (no instructions) conditions, older women reported higher perceived vulnerability and lower absent/exempt beliefs, and took more sunscreen than younger women. However, older women reported higher absent/exempt beliefs and higher sun-risk willingness than younger women in the affect condition.

Nanostructure-mediated transport of biologics across epithelial tissue: enhancing permeability via nanotopography.

Herein, we demonstrate that nanotopographical cues can be utilized to enable biologics >66 kDa to be transported across epithelial monolayers. When placed in contact with epithelial monolayers, nanostructured thin films loosen the epithelial barrier and allow for significantly increased transport of FITC-albumin, FITC-IgG, and a model therapeutic, etanercept. Our work highlights the potential to use drug delivery systems which incorporate nanotopography to increase the transport of biologics across epithelial tissue.