Corrigendum to "Inpatient costs of congenital heart surgery in China: results from the National Centre for Cardiovascular Diseases" [The Lancet Regional Health - Western Pacific 2023; 31:100623].

[This corrects the article DOI: 10.1016/j.lanwpc.2022.100623.].

Inpatient costs of congenital heart surgery in China: results from the National Centre for Cardiovascular Diseases.

Background: Economic data on congenital heart disease (CHD) in China are scarce. Therefore, this study aimed to explore the inpatient costs of congenital heart surgery and related healthcare policies from a hospital perspective. Method: We used data from the Chinese Database for Congenital Heart Surgery (CDCHS) to prospectively analyse the inpatient costs of congenital heart surgery from May 2018 to December 2020. The total expenditure was divided into 11 columns (medications, imaging, consumable items, surgery, medical cares, laboratory tests, therapy, examinations, medical services, accommodations, and others), and explored according to the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) category, year, different age group, and CHD complexity. Authority economic data (index for gross domestic product [GDP], GDP per capita, per capita disposable income and average annual exchange rate of 2020 Chinese Yuan against US dollar) were accessed via the National Bureau of Statistics of China to better describe the burden. In addition, potential factors contributing to the costs were also investigated by using generalised linear model. Findings: All values are presented in 2020 Chinese Yuan (¥). A total of 6568 hospitalisations were enrolled. The median of overall total expenditure was ¥64,900 (≈9409 US Dollar [USD], interquartile range [IQR]: ¥35,819), with the lowest in STAT 1 (¥57,014 ≈ 8266 USD, [IQR]: ¥16,774) and the highest in STAT 5 (¥194,862 ≈ 28,251 USD, [IQR]: ¥130,010). The median costs during the 2018 to 2020 period were ¥62,014 (≈8991 USD, [IQR]: ¥32,628), ¥64,846 (≈9401 USD, [IQR]: ¥34,469) and ¥67,867 (≈9839 USD, [IQR]: ¥41,496). Regarding to age, the median costs were highest in the ≤1 month group (¥144,380 ≈ 20,932 USD, [IQR]: ¥92,584). Age, STAT category, emergency, genetic syndrome, delay sternal closure, mechanical ventilation time, and complications were significantly contributed to the inpatient costs. Interpretation: For the first time, the inpatient costs of congenital heart surgery in China are delineated in detail. According to the results, CHD treatment has achieved significant progress in China, but it still causes substantial economic burden to both families and society. In addition, ascending trend of the inpatient costs was observed during the period of 2018-2020, and the neonatal was revealed to be the most challenging group. Funding: This study was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS,2020-I2M-C&T-A-009), Capital Health Research and Development of Special Fund (2022-1-4032), and The City University of Hong Kong New Research Initiatives/Infrastructure Support from Central (APRC, 9610589).

Personalised app-based relapse prevention of depressive and anxiety disorders in remitted adolescents and young adults: a protocol of the StayFine RCT.

INTRODUCTION: Youth in remission of depression or anxiety have high risks of relapse. Relapse prevention interventions may prevent chronicity. Aim of the study is therefore to (1) examine efficacy of the personalised StayFine app for remitted youth and (2) identify high-risk groups for relapse and resilience. METHOD AND ANALYSIS: In this Dutch single-blind parallel-group randomised controlled trial, efficacy of app-based monitoring combined with guided app-based personalised StayFine intervention modules is assessed compared with monitoring only. In both conditions, care as usual is allowed. StayFine modules plus monitoring is hypothesised to be superior to monitoring only in preventing relapse over 36 months. Participants (N=254) are 13-21 years and in remission of depression or anxiety for >2 months. Randomisation (1:1) is stratified by previous treatment (no treatment vs treatment) and previous episodes (1, 2 or >3 episodes). Assessments include diagnostic interviews, online questionnaires and monitoring (ecological momentary assessment with optional wearable) after 0, 4, 12, 24 and 36 months. The StayFine modules are guided by certified experts by experience and based on preventive cognitive therapy and ingredients of cognitive behavioural therapy. Personalisation is based on shared decision-making informed by baseline assessments and individual symptom networks. Time to relapse (primary outcome) is assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia-lifetime version diagnostic interview. Intention-to-treat survival analyses will be used to examine the data. Secondary outcomes are symptoms of depression and anxiety, number and duration of relapses, global functioning, and quality of life. Mediators and moderators will be explored. Exploratory endpoints are monitoring and wearable outcomes. ETHICS, FUNDING AND DISSEMINATION: The study was approved by METC Utrecht and is funded by the Netherlands Organisation for Health Research and Development (636310007). Results will be submitted to peer-reviewed scientific journals and presented at (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT05551468; NL8237.

Current perspectives on diffuse midline glioma and a different role for the immune microenvironment compared to glioblastoma.

Diffuse midline glioma (DMG), formerly called diffuse intrinsic pontine glioma (DIPG), is a high-grade malignant pediatric brain tumor with a near-zero survival rate. To date, only radiation therapy provides marginal survival benefit; however, the median survival time remains less than a year. Historically, the infiltrative nature and sensitive location of the tumor rendered surgical removal and biopsies difficult and subsequently resulted in limited knowledge of the disease, as only post-mortem tissue was available. Therefore, clinical decision-making was based upon experience with the more frequent and histologically similar adult glioblastoma (GBM). Recent advances in tissue acquisition and molecular profiling revealed that DMG and GBM are distinct disease entities, with separate tissue characteristics and genetic profiles. DMG is characterized by heterogeneous tumor tissue often paired with an intact blood-brain barrier, possibly explaining its resistance to chemotherapy. Additional profiling shed a light on the origin of the disease and the influence of several mutations such as a highly recurring K27M mutation in histone H3 on its tumorigenesis. Furthermore, early evidence suggests that DMG has a unique immune microenvironment, characterized by low levels of immune cell infiltration, inflammation, and immunosuppression that may impact disease development and outcome. Within the tumor microenvironment of GBM, tumor-associated microglia/macrophages (TAMs) play a large role in tumor development. Interestingly, TAMs in DMG display distinct features and have low immune activation in comparison to other pediatric gliomas. Although TAMs have been investigated substantially in GBM over the last years, this has not been the case for DMG due to the lack of tissue for research. Bit by bit, studies are exploring the TAM-glioma crosstalk to identify what factors within the DMG microenvironment play a role in the recruitment and polarization of TAMs. Although more research into the immune microenvironment is warranted, there is evidence that targeting or stimulating TAMs and their factors provide a potential treatment option for DMG. In this review, we provide insight into the current status of DMG research, assess the knowledge of the immune microenvironment in DMG and GBM, and present recent findings and therapeutic opportunities surrounding the TAM-glioma crosstalk.

Persistent post-thyroidectomy hypoparathyroidism: A multicenter retrospective cohort study.

BACKGROUND AND OBJECTIVE: The reported incidence of persistent hypoparathyroidism varies widely, and consensus on a definition is lacking. The objective was to evaluate the real-life incidence of persistent hypoparathyroidism by investigating a new pragmatic definition. METHODS: This retrospective multicenter cohort study evaluated the effect of different definitions for persistent hypoparathyroidism on the incidence of hypoparathyroidism. In addition, risk factors for hypoparathyroidism were analyzed. RESULTS: In total, 749 patients were included. Using the new pragmatic definition, we report an incidence of 7.9% of persistent hypoparathyroidism. When applying other commonly used definitions, incidence varied between 11.8% and 22.1%. Risk factors were parathyroid autotransplantation, presence of another surgical complication, and low postoperative serum calcium. CONCLUSIONS: Our data show that the incidence of persistent hypoparathyroidism in the literature may vary through the use of different definitions. This study indicates that a new pragmatic definition of persistent hypoparathyroidism has the potential to enable unbiased comparison between studies.

The cost-effectiveness of bivalent, quadrivalent, and nine-valent HPV vaccination in Asia: a systematic review.

PURPOSE: The aim of this study was to systematically review the cost-effectiveness of HPV vaccination in Asia. METHODS: We performed a systematic review of papers indexed in PubMed, Scopus, and Web of Science covering the period from 1 January 2000 to 13 August 2020. RESULTS: Sixteen studies were included in the review. Half of them (8 studies) evaluated the cost-effectiveness of HPV vaccination in high-income countries and regions (HICs) while the other eight studies were set in low- and middle-income countries and regions (LMICs). In HICs, the implementation of bivalent, quadrivalent and nine-valent HPV vaccination was all shown to be cost-effective. Most studies (7/8) also showed that it was cost-effective to implement bivalent, quadrivalent, and nine-valent HPV vaccines in LMICs. However, one study concluded that it was not cost-effective to implement bivalent HPV vaccination in Thailand. CONCLUSION: In general, the implementation of bivalent, quadrivalent and nine-valent HPV vaccination for adolescent girls was cost-effective in both high-income countries and regions and low- and middle-income countries and regions in Asia. Policy makers in HICs could consider expanding the target vaccinated population, while for LMICs it is essential to reduce HPV vaccine price to a level at which the implementation of HPV vaccination is cost-effective.

High Systemic Immune Inflammation Index Is Associated With Low Skeletal Muscle Quantity in Resectable Pancreatic Ductal Adenocarcinoma.

Background and Aims: Failing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC. Methods: Patients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected. Results: A total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (≥900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes. Conclusion: This study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients' survival outcomes.

Plasma levels of platelet-derived microvesicles are associated with risk of future venous thromboembolism.

BACKGROUND: Microvesicles (MVs) are small double-membrane encapsulated particles shed from cells. Case-control studies have reported elevated plasma levels of platelet-derived MVs (PDMVs) in patients with venous thromboembolism (VTE). However, it is not known whether high PDMV levels is a risk factor or a consequence of the acute VTE event. OBJECTIVES: To investigate the association between PDMVs in plasma and risk of future incident VTE. METHODS: We performed a population-based nested case-control study with 314 VTE cases and 705 age- and sex-matched controls (from The Tromsø Study) to investigate the association between the proportion of PDMVs (PDMVs%) in plasma and risk of future incident VTE. MVs isolated from plasma sampled at baseline (i.e., before VTE) were stained for platelet markers and analyzed by flow cytometry. PDMVs% were defined as the number of PDMVs divided by the total number of MVs. Odds ratios (ORs) with 95% confidence intervals (CI) for VTE risk were estimated across quartiles of PDMVs%. RESULTS: Subjects with PDMVs% in the highest quartile had an OR for VTE of 1.78 (95% CI: 1.21-2.64) and 1.99 (95% CI: 1.24-3.26) for provoked VTE, compared to those in the lowest quartile. The association was moderately affected by multivariable adjustment for age, sex, body mass index, C-reactive protein, platelet count, and cancer. The OR for VTE was higher when the time between blood sampling and event was shorter. CONCLUSIONS: Our results show that high proportions of PDMVs are associated with future risk of incident VTE and imply a role of platelet activation in the pathogenesis of VTE.

Melkersson-Rosenthal syndrome in the context of sarcoidosis: a case report.

BACKGROUND: Melkersson-Rosenthal syndrome is a rare disease characterized by the triad of recurrent orofacial swelling with facial paralysis and fissured dorsal tongue. Histologically, noncaseating granulomatous inflammation occurs that confirms the diagnosis. Overlaps between granulomatous diseases such as sarcoidosis and Crohn's disease are described. Systemic corticosteroid therapy is the treatment of choice for acute attacks. CASE PRESENTATION: We here present a case of a 59-year-old White woman suffering from Melkersson-Rosenthal syndrome with a past history of sarcoidosis on therapy with leflunomide in combination with low-dose tacrolimus successfully treated with the anti-leprosy drug clofazimine after failure of systemic steroid therapy. CONCLUSIONS: We propose clofazimine as an alternative treatment in steroid-refractory cases.

Maternal tobacco exposure and health-related quality of life during pregnancy: a national-based study of pregnant women in China.

BACKGROUND: With the increase of the number of smokers, tobacco exposure among pregnant women is becoming more and more common. Pregnant women exposed to first-hand smoke and second-hand smoke are susceptible to physiological and psychological health issues has been proved in previous studies. Nevertheless, there are no enough studies focus on the impact of third-hand smoke during pregnancy. This study aimed to assess and compare health-related quality of life for pregnant women with exposure to first-hand smoke, second-hand smoke, third-hand smoke and non-exposure to tobacco in mainland China. METHODS: National-based cross-sectional study is based on a questionnaire survey which collects information including demographics, smoking behaviors and self-evaluation. All questionnaires were delivered and collected from August to September 2019. EuroQol group's visual analog scale and EuroQoL Five-dimension Questionnaire were used to collect data in mainland China. RESULTS: Totally, 15,682 pregnant women were included in this study, among which non-exposure to smoke were 7564 (48.2%), exposed to first-hand smoke, second-hand smoke and third-hand smoke were 89 (0.6%), 2349 (15.0%), and 5680 (36.2%) respectively. Pregnant women without tobacco exposure had the highest EuroQol group's visual analog scale score (mean value = 85.4[SD = 14.0]), while those with first-hand smoke had the lowest score (mean value = 77.4[SD = 22.2]). Among all five dimensions of EuroQoL Five-dimension Questionnaire, there were significant differences of EQ-index among groups with different tobacco exposure in usual activity and anxiety or depression dimensions (p < 0.001). CONCLUSIONS: Third-hand smoke exposure had close relationship with low health-related quality of life in pregnant women. Moreover, second-hand smoke exposure significantly led more problems on mental dimension of pregnant women.

Efficacy of Low-Carbohydrate Ketogenic Diet as an Adjuvant Cancer Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The role of low-carbohydrate ketogenic diet (LCKD) as an adjuvant therapy in antitumor treatment is not well established. This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to investigate the efficacy of LCKD as an adjuvant therapy in antitumor treatment compared to non-ketogenic diet in terms of lipid profile, body weight, fasting glucose level, insulin, and adverse effects; Methods: In this study, databases such as PubMed, Web of Science, Scopus, CINAHL, and Cochrane trials were searched. Only RCTs that involved cancer participants that were assigned to dietary interventions including a LCKD group and a control group (any non-ketogenic dietary intervention) were selected. Three reviewers independently extracted the data, and the meta-analysis was performed using a fixed effects model or random effects model depending on the I2 value or p-value; Results: A total of six articles met the inclusion/exclusion criteria. In the overall analysis, the post-intervention results = standard mean difference, SMD (95% CI) showed total cholesterol (TC) level = 0.25 (-0.17, 0.67), HDL-cholesterol = -0.07 (-0.50, 0.35), LDL-cholesterol = 0.21 (-0.21, 0.63), triglyceride (TG) = 0.09 (-0.33, 0.51), body weight (BW) = -0.34 (-1.33, 0.65), fasting blood glucose (FBG) = -0.40 (-1.23, 0.42) and insulin = 0.11 (-1.33, 1.55). There were three outcomes showing significant results in those in LCKD group: the tumor marker PSA, p = 0.03, the achievement of ketosis p = 0.010, and the level of satisfaction, p = 0.005; Conclusions: There was inadequate evidence to support the beneficial effects of LCKDs on antitumor therapy. More trials comparing LCKD and non-KD with a larger sample size are necessary to give a more conclusive result.

Atmospheric H2S exposure does not affect stomatal aperture in maize.

MAIN CONCLUSION: Stomatal aperture in maize is not affected by exposure to a subtoxic concentration of atmospheric H2S. At least in maize, H2S, thus, is not a gaseous signal molecule that controls stomatal aperture. Sulfur is an indispensable element for the physiological functioning of plants with hydrogen sulfide (H2S) potentially acting as gasotransmitter in the regulation of stomatal aperture. It is often assumed that H2S is metabolized into cysteine to stimulate stomatal closure. To study the significance of H2S for the regulation of stomatal closure, maize was exposed to a subtoxic atmospheric H2S level in the presence or absence of a sulfate supply to the root. Similar to other plants, maize could use H2S as a sulfur source for growth. Whereas sulfate-deprived plants had a lower biomass than sulfate-sufficient plants, exposure to H2S alleviated this growth reduction. Shoot sulfate, glutathione, and cysteine levels were significantly higher in H2S-fumigated plants compared to non-fumigated plants. Nevertheless, this was not associated with changes in the leaf area, stomatal density, stomatal resistance, and transpiration rate of plants, meaning that H2S exposure did not affect the transpiration rate per stoma. Hence, it did not affect stomatal aperture, indicating that, at least in maize, H2S is not a gaseous signal molecule controlling this aperture.

Sarcoidosis exosomes stimulate monocytes to produce pro-inflammatory cytokines and CCL2.

Pulmonary sarcoidosis has unknown etiology, a difficult diagnostic procedure and no curative treatment. Extracellular vesicles including exosomes are nano-sized entities released from all cell types. Previous studies of exosomes from bronchoalveolar lavage fluid (BALF) of sarcoidosis patients have revealed pro-inflammatory components and abilities, but cell sources and mechanisms have not been identified. In the current study, we found that BALF exosomes from sarcoidosis patients, but not from healthy individuals, induced a dose-dependent elevation of intracellular IL-1ß in monocytes. Analyses of supernatants showed that patient exosomes also induced release of IL-1ß, IL-6 and TNF from both PBMCs and enriched monocytes, suggesting that the observed effect is direct on monocytes. The potently chemotactic chemokine CCL2 was induced by exosomes from a subgroup of patients, and in a blocking assay the exosome-induced CCL2 was reduced for 13 out of 19 patients by the asthma drug Montelukast, a cysteinyl leukotriene receptor antagonist. Further, reactive oxygen species generation by PBMCs was induced to a higher degree by patient exosomes compared to healthy exosomes. These findings add to an emerging picture of exosomes as mediators and disseminators of inflammation, and open for further investigations of the link between CCL2 and exosomal leukotrienes in sarcoidosis.

Main and interacting effects of physical activity and sedentary time on older adults' BMI: The moderating roles of socio-demographic and environmental attributes.

OBJECTIVES: Our first aim was to examine the main and interacting effects of accelerometer-based sedentary time (ST) and moderate-to-vigorous physical activity (MVPA) with BMI and the likelihood of being overweight/obese in Hong Kong and Ghent (Belgium) older adults. Second, we examined whether these main associations and interactions between MVPA and ST were moderated by socio-demographics (gender, education) and objective neighbourhood attributes supposed to be associated with healthy food intake (food outlet density, neighbourhood-level SES). Finally, we determined whether the associations and interactions were generalisable across study sites. METHODS: Data from the ALECS (Hong Kong) and BEPAS Seniors studies (Ghent), two comparable observational studies, were used. Older adults (n = 829, 65+) provided self-reported socio-demographic information and objective MVPA and ST data using Actigraph accelerometers. Annual household income data and GIS software were used to assess neighbourhood-level SES and food outlet density. Generalised additive mixed models were conducted in R. RESULTS: ST was linearly and positively related to both weight outcomes in the overall sample, while MVPA was not. The overall-sample analyses including the two-way interaction between MVPA and ST showed no interactions between these behaviours on weight outcomes. Three site-specific findings were identified, showing distinct associations in Hong Kong compared to Ghent. Study site moderated the interaction between ST and MVPA on both weight outcomes, the interaction between education and ST on both weight outcomes and the interaction between the number of food outlets and ST on being overweight/obese. CONCLUSIONS: The country-specific effects confirm the cultural dependency and complexity of the associations between PA, ST and weight outcomes. Future longitudinal international studies including older adults from multiple regions assessing PA, ST, weight outcomes and dietary intake should be encouraged. Such studies are needed to refine the recommendations regarding ST and PA in older adults in light of preventing overweight and obesity.

The association between secondhand smoke and childhood asthma: A systematic review and meta-analysis.

BACKGROUND: Secondhand smoke (SHS) exposure can trigger asthma exacerbations in children. Different studies have linked increased asthma symptoms and even deaths in children with SHS, but the risk has not been quantified uniformly across studies. We aimed to investigate the role of SHS exposure as a risk factor of asthma among children. METHODS: We performed a systematic review in PubMed, Scopus, and Google Scholar from June 1975 to 10 March 2020. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk estimates and confidence intervals of all types of SHS exposure and childhood asthma. RESULTS: Of the 26 970 studies identified, we included 93 eligible studies (42 cross-sectional, 41 cohort, and 10 case-control) in the meta-analysis. There were significantly positive associations between SHS exposure and doctor-diagnosed asthma (OR = 1.24; 95% confidence interval (CI) = 1.20-1.28), wheezing (OR = 1.27; 95% CI = 1.23-1.32) and asthma-like syndrome (OR = 1.34; 95% CI = 1.34-1.64). The funnel plots of all three outcomes skewed to the right, indicating that the studies generally favor a positive association of the disease with tobacco exposure. Subgroup analysis demonstrated that younger children tended to suffer more from developing doctor-diagnosed asthma, but older children (adolescents) suffered more from wheezing. There was no evidence of significant publication or small study bias using Egger's and Begg's tests. CONCLUSION: The results show a positive association between prenatal and postnatal secondhand smoking exposure and the occurrence of childhood asthma, asthma-like syndrome, and wheezing. These results lend support to continued efforts to reduce childhood exposure to secondhand smoke.

Urban environments and objectively-assessed physical activity and sedentary time in older Belgian and Chinese community dwellers: potential pathways of influence and the moderating role of physical function.

BACKGROUND: Many studies have examined neighbourhood environmental correlates of older adults' physical activity (PA) but only a few focused on sedentary time (ST). Only a small proportion of these studies used objective measures of PA/ST, such as accelerometer-assessed PA/ST, and only a couple employed accelerometer cut-points appropriate for older adults. Furthermore, although older adults experience declines in physical function as they age, there is a dearth of information on the impact of the neighbourhood environment on PA/ST in individuals with different levels of physical function. METHODS: We used data from two extant cross-sectional studies conducted in Hong Kong (China) and Ghent (Belgium) (N = 829). Participants were recruited from pre-selected administrative units stratified by socio-economic status and walkability. Moderate-to-vigorous PA (MVPA) and ST were assessed for 7 days using accelerometers and cut-points developed for older adults. Objective neighbourhood environmental attributes within 400 m and 1 km buffers surrounding participants' homes were quantified using Geographic Information Systems data. Lower extremity physical function was objectively assessed. Socio-demographic information was collected via interviews. Total, direct and indirect (mediated) effects of environmental attributes on MVPA and ST were estimated using generalised additive mixed models and the joint-significant test. RESULTS: Commercial/civic destination density and number of parks within 1 km from home showed positive total and direct effects on MVPA, and public transport density showed negative total and direct effects on ST, which were consistent across cities and physical function levels. The total and direct effects of residential density on MVPA depended on physical function, and those of residential density on ST differed by city. A complex network of potential inconsistent pathways linking all environmental attributes to MVPA and ST in the whole sample or in subgroups of participants was revealed. DISCUSSION: Access to parks and commercial/civic destinations appear to support older adults' MVPA in different geographical and cultural contexts and irrespective of their physical function level. By supporting MVPA, these characteristics also contribute to a reduction in ST. The potential effects of public transport, recreational facilities and residential density are less straightforward and point at inconsistent effects that may depend on the geographical context and level of physical function.

Exosomes and cells from lung cancer pleural exudates transform LTC4 to LTD4, promoting cell migration and survival via CysLT1.

Tumor-derived exosomes can modulate the cancer microenvironment and induce metastatic spread. Exosomes may carry enzymes for leukotriene (LT) biosynthesis, but the role of exosomal LTs has not been studied in cancer. We isolated exosomes and malignant cells from pleura exudates from 14 patients with non-small cell lung cancer. Lipidomic profiles, migration and apoptosis were determined. Both exosomes and primary cancer cells contained γ-glutamyl transpeptidase 1 (GGT-1) and avidly transformed exogenous LTC4 to pro-tumorigenic LTD4, for the cells to levels 100-fold above their endogenous CysLT production. This suggests that cancer cells promote their own survival via LTD4 if supplied with LTC4, which in the exudates was produced by monocytic cells. Furthermore, exosomes promoted migration of cancer cells, which was counteracted by the CysLT1 antagonist montelukast. Montelukast also induced apoptosis of cancer cells, and this was partially inhibited by exosomes. Our results demonstrate how cancer cells and exosomes, together with monocytic cells in lung cancer tissue, can produce high amounts of LTD4, to stimulate cancer cell migration and survival. This suggests that part of the pro-metastatic effect of exosomes is mediated by the leukotriene machinery, further supporting the use of CysLT1 antagonists for lung cancer therapy.

Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study.

BACKGROUND: Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis. METHODS: We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with non-immunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group). FINDINGS: Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0·0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5·19; 95% CI 2·63-10·26; p<0·0001), along with a higher APACHE II score, male sex, and use of corticosteroids. INTERPRETATION: Influenza was identified as an independent risk factor for invasive pulmonary aspergillosis and is associated with high mortality. Future studies should assess whether a faster diagnosis or antifungal prophylaxis could improve the outcome of influenza-associated aspergillosis. FUNDING: None.

Exosomes from antigen-pulsed dendritic cells induce stronger antigen-specific immune responses than microvesicles in vivo.

Extracellular vesicles (EV), including exosomes and microvesicles (MV), represent a rapidly expanding field of research with diagnostic and therapeutic applications. Although many aspects of EV function remain to be revealed and broad investigations are warranted, most published findings focus on only one vesicle category or a non-separated mix of EVs. In this paper, we investigated both MVs and exosomes from Ovalbumin (OVA)-pulsed dendritic cells for their immunostimulatory potential side-by-side in vivo. Only exosomes induced antigen-specific CD8+ T-cells, and were more efficient than MVs in eliciting antigen-specific IgG production. Further, mainly exosome-primed mouse splenocytes showed significant ex vivo interferon gamma production in response to antigen restimulation. Exosomes carried high levels of OVA, while OVA in MVs was barely detectable, which could explain the more potent antigen-specific response induced by exosomes. Moreover, exosomes induced increased germinal center B cell proportions, whereas MVs had no such effect. Immunisation with both vesicle types combined showed neither inhibitory nor synergistic effects. We conclude that DC-derived MVs and exosomes differ in their capacity to incorporate antigen and induce immune responses. The results are of importance for understanding the role of EVs in vivo, and for future design of vesicle-based immunotherapies and vaccines.

Pulmonary Extracellular Vesicles as Mediators of Local and Systemic Inflammation.

Cells of the airways are constantly exposed to environmental hazards including cigarette smoke, irritants, pathogens, and mechanical insults. Maintaining barrier integrity is vital, and mounting responses to threats depends on intercellular communication. Extracellular vesicles (EVs), including exosomes and microvesicles, are major signal mediators between cells, shuttling cargo in health and disease. Depending on the state of the originating cells, EVs are capable of inducing proinflammatory effects including antigen presentation, cellular migration, apoptosis induction, and inflammatory cytokine release. Cells of the airways release EVs, which can be found in bronchoalveolar lavage fluid. EVs of the airways can support inflammation in the lung, but may also exit into the circulation and carry a cocktail of pro-inflammatory molecules to recipient cells in distant organs. In this review, we discuss the possibility that EVs originating from the airways contribute to dissemination of inflammation in both lung disorders and systemic inflammatory conditions.