Explore the vast range of titles available.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease, especially in young children. Despite its global impact on healthcare, related to its high prevalence and its association with significant morbidity, the current therapy is still mostly supportive. Moreover, while more than 50 years have passed since the first trial of an RSV vaccine (which unfortunately caused enhanced RSV disease), no vaccine has been approved for RSV prevention. In the last two decades, our understanding of the pathogenesis and immunopathology of RSV have continued to evolve, leading to significant advancements in RSV prevention strategies. These include both the development of new potential vaccines and the successful implementation of passive immunization, which, together, will provide coverage from infancy to old age. In this review, we provide an update of the current treatment options for acute disease (RSV-specific and -non-specific) and different therapeutic approaches focusing on RSV prevention.

Pre-school children spend an average of two-hours daily using screens. We examined associations between screen-time on pre-school behavior using data from the Canadian Healthy Infant Longitudinal Development (CHILD) study. CHILD participant parents completed the Child Behavior Checklist (CBCL) at five-years of age. Parents reported their child's total screen-time including gaming and mobile devices. Screen-time was categorized using the recommended threshold of two-hours/day for five-years or one-hour/day for three-years. Multiple linear regression examined associations between screen-time and externalizing behavior (e.g. inattention and aggression). Multiple logistic regression identified characteristics of children at risk for clinically significant externalizing problems (CBCL T-score≥65). Screen-time was available for over 95% of children (2,322/2,427) with CBCL data. Mean screen-time was 1·4 hours/day (95%CI 1·4, 1·5) at five-years and 1·5 hours/day (95%CI: 1·5, 1·6) at three-years. Compared to children with less than 30-minutes/day screen-time, those watching more than two-hours/day (13·7%) had a 2·2-point increase in externalizing T-score (95%CI: 0·9, 3·5, p≤0·001); a five-fold increased odd for reporting clinically significant externalizing problems (95%CI: 1·0, 25·0, p = 0·05); and were 5·9 times more likely to report clinically significant inattention problems (95%CI: 1·6, 21·5, p = 0·01). Children with a DSM-5 ADHD T-score above the 65 clinical cut-off were considered to have significant ADHD type symptoms (n = 24). Children with more than 2-hours of screen-time/day had a 7·7-fold increased risk of meeting criteria for ADHD (95%CI: 1·6, 38·1, p = 0·01). There was no significant association between screen-time and aggressive behaviors (p>0.05). Increased screen-time in pre-school is associated with worse inattention problems.

Allergic diseases affect millions of people worldwide. An increase in their prevalence has been associated with alterations in the gut microbiome, i.e., the microorganisms and their genes within the gastrointestinal tract. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. Here we show, using deeply phenotyped participants in the CHILD birth cohort ( n  = 1115), that there are early-life influences and microbiome features which are uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD, n  = 367), asthma (As, n  = 165), food allergy (FA, n  = 136), and allergic rhinitis (AR, n  = 187). In a subset with shotgun metagenomic and metabolomic profiling ( n  = 589), we discover that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD p  = 0.000014; As p  = 0.0073; FA p  = 0.00083; and AR p  = 0.0021). Extending this, we find a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (β indirect  = −2.28; p  = 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease. Here, using participants in the CHILD birth cohort, the authors reveal that impaired 1-year microbiota maturation may be universal to 5-year pediatric allergies, mediated by functional and metabolic imbalances of compromised mucous integrity, elevated oxidative activity, decreased fermentation, and elevated trace amines.

Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options 1 . RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV 2 and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia 3 , 4 . Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection. Respiratory syncytial virus enters cells by binding to cell-surface IGFR1, which activates PKCζ and induces trafficking of the NCL coreceptor to the RSV particles at the cell surface.

Respiratory syncytial virus (RSV) is a common airway pathogen that can cause severe illness, yet there is no vaccine or effective therapy available. Tayyari et al . now report that nucleolin is a cellular receptor for RSV and suggest that nucleolin-targeting strategies could be developed to inhibit RSV infection and protect against disease. Human respiratory syncytial virus (RSV) causes a large burden of disease worldwide 1 . There is no effective vaccine or therapy, and the use of passive immunoprophylaxis with RSV-specific antibodies is limited to high-risk patients 2 , 3 , 4 , 5 . The cellular receptor (or receptors) required for viral entry and replication has yet to be described; its identification will improve understanding of the pathogenesis of infection and provide a target for the development of novel antiviral interventions. Here we show that RSV interacts with host-cell nucleolin via the viral fusion envelope glycoprotein and binds specifically to nucleolin at the apical cell surface in vitro . We observed decreased RSV infection in vitro in neutralization experiments using nucleolin-specific antibodies before viral inoculation, in competition experiments in which virus was incubated with soluble nucleolin before inoculation of cells, and upon RNA interference (RNAi) to silence cellular nucleolin expression. Transfection of nonpermissive Spodoptera frugiperda Sf9 insect cells with human nucleolin conferred susceptibility to RSV infection. RNAi-mediated knockdown of lung nucleolin was associated with a significant reduction in RSV infection in mice ( P = 0.0004), confirming that nucleolin is a functional RSV receptor in vivo .

Understanding the factors that influence smoking cessation among young people is crucial for planning targeted cessation approaches. The objective of this review was to comprehensively summarize evidence for predictors of different smoking cessation related behaviors among young people from currently available systematic reviews. We searched six databases and reference lists of the included articles for studies published up to October 20, 2023. All systematic reviews summarizing predictors of intention to quit smoking, quit attempts, or smoking abstinence among people aged 10–35 years were included. We excluded reviews on effectiveness of smoking cessation intervention; smoking prevention and other smoking behaviors; cessation of other tobacco products use, dual use, and polysubstance use. We categorized the identified predictors into 5 different categories for 3 overlapping age groups. JBI critical appraisal tool and GRADE-CERqual approach were used for quality and certainty assessment respectively. A total of 11 systematic reviews were included in this study; all summarized predictors of smoking abstinence/quit attempts and two also identified predictors of intention to quit smoking. Seven reviews had satisfactory critical appraisal score and there was minimal overlapping between the reviews. We found 4 ‘possible’ predictors of intention to quit smoking and 119 predictors of smoking abstinence/quit attempts. Most of these 119 predictors were applicable for ~10–29 years age group. We had moderate confidence on the ‘probable’, ‘possible’, ‘insufficient evidence’, and ‘inconsistent direction’ predictors and low confidence on the ‘probably unrelated’ factors. The ‘probable’ predictors include a wide variety of socio-demographic factors, nicotine dependence, mental health, attitudes, behavioral and psychological factors, peer and family related factors, and jurisdictional policies. These predictors can guide improvement of existing smoking cessation interventions or planning of new targeted intervention programs. Other predictors as well as predictors of intention to quit smoking need to be further investigated among adolescents and young adults separately.

Matrix metalloproteinases (MMPs) normally act extracellularly. Now Marchant et al . report an unexpected nuclear activity for MMP-12 in virus-infected cells in regulating transcription of the gene encoding IκBα and affecting secretion of interferon-α. Interferon-α (IFN-α) is essential for antiviral immunity, but in the absence of matrix metalloproteinase-12 (MMP-12) or IκBα (encoded by NFKBIA ) we show that IFN-α is retained in the cytosol of virus-infected cells and is not secreted. Our findings suggest that activated IκBα mediates the export of IFN-α from virus-infected cells and that the inability of cells in Mmp12 −/− but not wild-type mice to express IκBα and thus export IFN-α makes coxsackievirus type B3 infection lethal and renders respiratory syncytial virus more pathogenic. We show here that after macrophage secretion, MMP-12 is transported into virus-infected cells. In HeLa cells MMP-12 is also translocated to the nucleus, where it binds to the NFKBIA promoter, driving transcription. We also identified dual-regulated substrates that are repressed both by MMP-12 binding to the substrate's gene exons and by MMP-12–mediated cleavage of the substrate protein itself. Whereas intracellular MMP-12 mediates NFKBIA transcription, leading to IFN-α secretion and host protection, extracellular MMP-12 cleaves off the IFN-α receptor 2 binding site of systemic IFN-α, preventing an unchecked immune response. Consistent with an unexpected role for MMP-12 in clearing systemic IFN-α, treatment of coxsackievirus type B3–infected wild-type mice with a membrane-impermeable MMP-12 inhibitor elevates systemic IFN-α levels and reduces viral replication in pancreas while sparing intracellular MMP-12. These findings suggest that inhibiting extracellular MMP-12 could be a new avenue for the development of antiviral treatments.

Previously developed cesarean section (CS) and emergency CS prediction tools use antenatal and intrapartum risk factors. We aimed to develop a predictive model for the risk of emergency CS before the onset of labour utilizing antenatal obstetric and non-obstetric factors. We completed a secondary analysis of data collected from the CHILD Cohort Study. The analysis was limited to term ([greater than or equal to]37 weeks), singleton pregnant women with cephalic presentation. The sample was divided into a training and validation dataset. The emergency CS prediction model was developed in the training dataset and the performance accuracy was assessed by the area under the receiver operating characteristic curve(AUC) of the receiver operating characteristic analysis (ROC). Our final model was subsequently evaluated in the validation dataset. The participant sample consisted of 2,836 pregnant women. Mean age of participants was 32 years, mean BMI of 25.4 kg/m2 and 39% were nulliparous. 14% had emergency CS delivery. Each year of increasing maternal age increased the odds of emergency CS by 6% (adjusted Odds Ratio (aOR 1.06,1.02-1.08). Likewise, there was a 4% increase odds of emergency CS for each unit increase in BMI (aOR 1.04,1.02-1.06). In contrast, increase in maternal height has a negative association with emergency CS. The final emergency CS delivery predictive model included six variables (hypertensive disorders of pregnancy, antenatal depression, previous vaginal delivery, age, height, BMI). The AUC for our final prediction model was 0.74 (0.72-0.77) in the training set with a similar AUC in the validation dataset (0.77; 0.71-0.82). The developed and validated emergency CS delivery prediction model can be used in counselling prospective parents around their CS risk and healthcare resource planning. Further validation of the tool is suggested.

Respiratory syncytial virus (RSV) is a common childhood infection that in young infants can progress into severe bronchiolitis and pneumonia. Disease pathogenesis results from both viral mediated and host immune processes of which alveolar macrophages play an important part. Here, we investigated the role of different types of alveolar macrophages on RSV infection using an in vitro co-culture model involving primary tissue-derived human bronchial epithelial cells (HBECs) and human blood monocyte-derived M0-like, M1-like, or M2-like macrophages. It was hypothesized that the in vitro model would recapitulate previous in vivo findings of a protective effect of macrophages against RSV infection. It was found that macrophages maintained their phenotype for the 72-hour co-culture time period and the bronchial epithelial cells were unaffected by the macrophage media. HBEC infection with RSV was decreased by M1-like macrophages but enhanced by M0- or M2-like macrophages. The medium used during the co-culture also impacted the outcome of the infection. This work demonstrates that alveolar macrophage phenotypes may have differential roles during epithelial RSV infection, and demonstrates that an in vitro co-culture model could be used to further investigate the roles of macrophages during bronchial viral infection.