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Nociceptive information is detected and transmitted by neurons in the DRG. Recently, single-cell RNA sequencing has revealed the molecular profile of various cell types, including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation. Here, we found that secreted modular calcium-binding protein 2 (SMOC2) was secreted by fibroblasts to become a component of basement membrane and envelop the unit consisting of DRG neurons and attached satellite glial cells. KO ofSmoc2in both sexes of mice led to increased neuronal clusters and decreased mechanical threshold, but unchanged noxious thermal response. Knockdown ofSmoc2in the DRG phenocopied the behavioral performance bySmoc2KO in both sexes of mice.In vivocalcium imaging showed thatSmoc2KO increased coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli, which was reversed by DRG injection of SMOC2. Importantly, SMOC2 interacted with P2X7 receptor (P2X7R) and suppressed ATP-induced activation in HEK293 cells expressing this receptor. Injection of A740003, an antagonist of P2X7R, to the DRG reduced coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli but did not further enhance the SMOC2-inhibited effect. Furthermore, peripheral inflammation resulted in a decreased SMOC2 and increased neuronal clusters. DRG injection of SMOC2 inhibited the neuronal coupling resulted from peripheral inflammation. This study reveals a specific role of fibroblastic SMOC2 in suppressing mechanical nociception through inhibiting the communication of adjacent DRG neurons, which provides an important mechanism of fibroblasts in nociceptive regulation.SIGNIFICANCE STATEMENTThe function of fibroblastic molecules is rarely noticed in the regulation of nociceptive sensation. Here, we reveal that fibroblastic SMOC2 is secreted to be a component of basement membrane and surrounded the unit consisting of DRG neuron and attached satellite glial cells. SMOC2 is required for maintaining the basal mechanical nociceptive threshold in the DRG. Loss of SMOC2 leads to the increased coupled activation of adjacent DRG neurons induced by noxious mechanical stimuli. Peripheral inflammation causes decreased fibroblast cells and SMOC2, which may result in the increase of coupled activation of adjacent DRG neurons. Mechanistically, SMOC2 interacts with and suppresses satellite glial P2X7 receptor to inhibit the coupled activation of adjacent DRG neurons.

Background Since the widespread adoption of palivizumab prophylaxis in Europe, there have been a number of clinical practice guidelines (CPGs) published for the prevention of respiratory syncytial virus (RSV) infection in children. The aim of this systematic review was to identify CPGs for the prevention of RSV infection across Europe. Methods We performed a systematic literature search and contacted European influenza and respiratory virus networks and public health institutions, to identify national CPGs for the prevention of RSV infection. The Reporting Items for practice Guidelines in Healthcare (RIGHT) Statement checklist was applied to extract data and review the quality of reporting. Results A total of 20 national CPGs were identified, all published between 2000 and 2018. The greatest discrepancy between guidelines was the recommendations for palivizumab prophylaxis for premature infants, with recommendations varying by gestational age. All guidelines recommended or considered the use of palivizumab in infants with bronchopulmonary dysplasia, 85% (n = 17) in children with congenital heart disease (CHD), and 60% (n = 12) in children with severe combined immunodeficiency. Conclusions We recommend that agencies publishing RSV prevention guidelines adopt the RIGHT reporting requirements when updating these guidelines to improve the presentation of the evidence-base for decisions.

Background Respiratory syncytial virus (RSV) is the most common viral pathogen associated with acute lower respiratory infections (ALRIs), with significant childhood morbidity and mortality worldwide. Estimates reporting RSV-associated ALRI (RSV-ALRI) severity in children with congenital heart disease (CHD) are lacking, thus warranting the need to summarize the available data. We identified relevant studies to summarize the findings and conducted a meta-analysis of available data on RSV-associated ALRI hospitalizations in children aged Methods We conducted a systematic search of existing relevant literature and identified studies reporting hospitalization of children aged Results We included 18 studies that met our strict eligibility criteria. The risk of severe RSV-ALRI (odds ratio, 2.2; 95% confidence interval [CI], 1.6–2.8), the rate of hospitalization (incidence rate ratio, 2.8; 95% CI, 1.9–4.1), and the case-fatality ratio (risk ratio [RR], 16.5; 95% CI, 13.7–19.8) associated with RSV-ALRI was higher among children with underlying CHD as compared to those without no CHD. The risk of admission to the intensive care unit (RR, 3.9; 95% CI, 3.4–4.5), need for supplemental oxygen therapy (RR, 3.4; 95% CI, .5–21.1), and need for mechanical ventilation (RR, 4.1; 95% CI, 2.1–8.0) was also higher among children with underlying CHD. Conclusion This is the most detailed review to show more-severe RSV-ALRI among children aged

BACKGROUND: Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (

BackgroundRecurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years.MethodsWe estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population.ResultsOverall, we included 41 studies. A statistically significant association was observed between early life RSV infection and subsequent childhood recurrent wheeze, in comparison to those who were healthy or those without respiratory symptoms: OR 3.05 (95% confidence interval [CI], 2.50–3.71) for 0 to ConclusionsFurther studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.

Background: Astaxanthin (AST) shows a large range of beneficial effects together with anti-cancer and antioxidation properties. Human Serum Albumin (HSA) is the most abundant protein in blood plasma which plays the role of a depot and transport protein for many exogenous compounds. However, whether HSA could enhance AST-induced cytotoxic effects in human ovarian cancer cells has not been examined to date. Objective: This study aims to explore the anticancer effect and the molecular mechanism of AST combine with HSA induced cytotoxicity in ovarian cancer SKOV3 cells. Methods: The ovarian cancer SKOV3 cells were treated by AST combined with HSA to study the effects of cell proliferation, cell morphology, cell cycle arrest, related protein expression, nuclear transfer, cell migration, and drug-resistant. Results: Our data confirmed that AST+HSA treatment enhanced the anticancer effects of AST, arrested G1 phase cell cycle and induced apoptosis in SKOV3 cells. AST+HSA induced apoptosis via mitochondrial apoptotic pathways was related to the increased ratio of Bcl-2/Bax and activation of caspase-3. Besides, exposure of cells to AST+HSA triggered the inactivation of NF-κB and activation p53 and MAPKs signaling pathways. Furthermore, AST+HSA significantly overcome the drug-resistant and inhibited the migration of SKOV3 cells. Conclusion: AST combined treatment with HSA considerably inhibited NF-κB expression and translocation to nucleus, thereby improving the AST-induced cytotoxic effect on SKOV3 cells. These findings may provide rationale to combine AST with HSA for the treatment of ovarian cancer.

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8–8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9–1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

Respiratory syncytial virus–associated acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in older adults aged ≥65 years. We aimed to identify all studies worldwide investigating the disease burden of RSV-ARI in this population. We estimated the community incidence, hospitalization rate, and in-hospital case-fatality ratio (hCFR) of RSV-ARI in older adults, stratified by industrialized and developing regions, using data from a systematic review of studies published between January 1996 and April 2018 and 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burdens in older adults with RSV-ARI in the community and in hospitals for that year. We estimated the number of in-hospital deaths due to RSV-ARI by combining hCFR data with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5 million episodes (95% confidence interval [CI], .3 million–6.9 million) of RSV-ARI in older adults in industrialized countries (data for developing countries were missing), and of these, approximately 14.5% (214 000 episodes; 95% CI, 100 000–459 000) were admitted to hospitals. The global number of hospital admissions for RSV-ARI in older adults was estimated at 336 000 hospitalizations (uncertainty range [UR], 186 000–614 000). We further estimated about 14 000 in-hospital deaths (UR, 5000–50 000) related to RSV-ARI globally. The hospital admission rate and hCFR were higher for those aged ≥65 years than for those aged 50–64 years. The disease burden of RSV-ARI among older adults is substantial, with limited data from developing countries. Appropriate prevention and management strategies are needed to reduce this burden.

BackgroundRespiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults.MethodsA literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946–October 2016. Nine articles were identified plus 9 from other sources.ResultsFrom observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection.ConclusionsFactors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

Systems biology can unravel complex biology but has not been extensively applied to human newborns, a group highly vulnerable to a wide range of diseases. We optimized methods to extract transcriptomic, proteomic, metabolomic, cytokine/chemokine, and single cell immune phenotyping data from, SCOPUS: ar.j, info:eu-repo/semantics/published

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9–18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4–15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3–41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7–13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0–4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report., The etiological roles of common respiratory viruses in acute respiratory infections in older adults are important and should be taken into consideration in disease burden estimates.

To evaluate the feasibility and safety of coronary artery angiography via femoral artery approach without heparin.Totally 1 400 consecutive patients undergoing coronary artery angiography with heparin were analyzed retrospectively in comparison with the data of 354 patients for coronary artery angiography without heparin.Success in selective coronary artery angiography was achieved in 99.3% of the patients in the non-heparin group, with the mean operation time of 17.9+/-11.3 min ranging from 8 min to 1 hour. Angiography identified coronary artery stenosis in 72.2% of the patients including 49.8% with multivessel involvement. Subcutaneous hematoma occurred in 25 (1.8%) of the patients, and 1 (0.07%) patient developed arterial and venous fistula and pseudoaneurysm at the puncture site, but other complications (retroperitoneal hematoma, acute myocardial infarction, stroke and peripheral artery thrombotic events) occurred neither during nor after the procedure. In the heparin group, 18 (5.1%) patients developed subcutaneous hematoma and 1 (0.2%) had arterial and venous fistula and pseudoaneurysm at the puncture site after angiography.Coronary artery angiography without heparin is both safe and feasible with only very low risk of complications.

Background Respiratory syncytial virus (RSV) is among the most important causes of acute lower respiratory tract infection (ALRI) in young children. We assessed the severity of RSV-ALRI in children less than 5 years old with bronchopulmonary dysplasia (BPD). Methods We searched for studies using EMBASE, Global Health, and MEDLINE. We assessed hospitalization risk, intensive care unit (ICU) admission, need for oxygen supplementation and mechanical ventilation, and in-hospital case fatality (hCFR) among children with BPD compared with those without (non-BPD). We compared the (1) length of hospital stay (LOS) and (2) duration of oxygen supplementation and mechanical ventilation between the groups. Results Twenty-nine studies fulfilled our inclusion criteria. The case definition for BPD varied substantially in the included studies. Risks were higher among children with BPD compared with non-BPD: RSV hospitalization (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7–4.2; P < .001), ICU admission (OR, 2.9; 95% CI, 2.3–3.5; P < .001), need for oxygen supplementation (OR, 4.2; 95% CI, .5–33.7; P = .175) and mechanical ventilation (OR, 8.2; 95% CI, 7.6–8.9; P < .001), and hCFR (OR, 12.8; 95% CI, 9.4–17.3; P < .001). Median LOS (range) was 7.2 days (4–23) (BPD) compared with 2.5 days (1–30) (non-BPD). Median duration of oxygen supplementation (range) was 5.5 days (0–21) (BPD) compared with 2.0 days (0–26) (non-BPD). The duration of mechanical ventilation was more often longer (>6 days) in those with BPD compared with non-BPD (OR, 11.9; 95% CI, 1.4–100; P = .02). Conclusions The risk of severe RSV disease is considerably higher among children with BPD. There is an urgent need to establish standardized BPD case definitions, review the RSV prophylaxis guidelines, and encourage more specific studies on RSV infection in BPD patients, including vaccine development and RSV-specific treatment.

Staphylococcus aureus capsular polysaccharides (CP) are important virulence factors under evaluation as vaccine antigens. Clinical S. aureus isolates have the biosynthetic capability to express either CP5 or CP8 and an understanding of the relationship between CP genotype/phenotype and S. aureus epidemiology is valuable. Using whole genome sequencing, the clonal relatedness and CP genotype were evaluated for disease-associated S. aureus isolates selected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T) to represent different geographic regions in the United States (US) during 2004 and 2009-10. Thirteen prominent clonal complexes (CC) were identified, with CC5, 8, 30 and 45 representing >80% of disease isolates. CC5 and CC8 isolates were CP type 5 and, CC30 and CC45 isolates were CP type 8. Representative isolates from prevalent CC were susceptible to in vitro opsonophagocytic killing elicited by anti-CP antibodies, demonstrating that susceptibility to opsonic killing is not linked to the genetic lineage. However, as not all S. aureus isolates may express CP, isolates representing the diversity of disease isolates were assessed for CP production. While approximately 35% of isolates (primarily CC8) did not express CP in vitro, CP expression could be clearly demonstrated in vivo for 77% of a subset of these isolates (n = 20) despite the presence of mutations within the capsule operon. CP expression in vivo was also confirmed indirectly by measuring an increase in CP specific antibodies in mice infected with CP5 or CP8 isolates. Detection of antigen expression in vivo in relevant disease states is important to support the inclusion of these antigens in vaccines. Our findings confirm the validity of CP as vaccine targets and the potential of CP-based vaccines to contribute to S. aureus disease prevention.