In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells is implicated in metastatic progression. Tumor-stroma cross-talk is often mediated through extracellular vesicles (EVs). We ...previously reported that EVs derived from cancer-associated stromal fibroblasts (CAFs) that are abundant in annexin A6 (ANXA6
EVs) support tumor cell aggressiveness in PDAC. Here, we found that the cell surface glycoprotein and tetraspanin CD9 is a key component of CAF-derived ANXA6
EVs for mediating this cross-talk. CD9 was abundant on the surface of ANXA6
CAFs isolated from patient PDAC samples and from various mouse models of PDAC. CD9 colocalized with CAF markers in the tumor stroma, and CD9 abundance correlated with tumor stage. Blocking CD9 impaired the uptake of ANXA6
EVs into cultured PDAC cells. Signaling pathway arrays and further analyses revealed that the uptake of CD9
ANXA6
EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT). Blocking either CD9 or p38 MAPK signaling impaired CD9
ANXA6
EV-induced cell migration and EMT in PDAC cells. Analysis of bioinformatic datasets indicated that CD9 abundance was an independent marker of poor prognosis in patients with PDAC. Our findings suggest that CD9-mediated stromal cell signaling promotes PDAC progression.
Aims
To describe the trends in anti‐infective use during pregnancy between 2010 and 2019 and determine whether they were prescribed according to drug foetal safety international classification ...systems.
Methods
We conducted a population‐based, nationwide study using the French national health data system including all pregnancies ended between 2010 and 2019. Anti‐infective agents were considered according to their pharmacological group and potential harmful risk using the Australian and Swedish classification systems. Prevalence rate was estimated annually and by trimester. Average annual percent change (AAPC) and 95% confidence intervals (CIs) were calculated using Joinpoint regression.
Results
Among 7 571 035 pregnancies, 3 027 031 (40.0%) received ≥1 antibacterial. This proportion decreased significantly from 41.5% in 2010 to 36.1% in 2019 (AAPC = −1.7%, 95%CI, −2.5 to −1.0%). Conversely, use of antiviral agents increased during the 10‐year study period for anti‐herpes simplex virus agents (AAPC = 4.4%, 3.7–5.2%), influenza agents (AAPC = 25.4%, 6.2–48.1%) and for HIV‐antiretroviral agents (AAPC = 1.3%, 0.6–2.0%). Use of influenza vaccine increased from 0.2% in 2010 to 4.2% in 2019 (AAPC = 49.7%, 39.3–60.9%). Among all pregnancies, 0.9% had been exposed to a potentially harmful anti‐infective agent increasing from 0.7% in 2010 to 1.2% in 2019 (AAPC = 6.4%, 4.4–8.5%).
Conclusion
Based on >7 million pregnancies identified from French nationwide data, this study showed that antibacterials are frequently prescribed during pregnancy although their use has decreased over the past 10 years. Our results suggest that anti‐infective agents are generally prescribed in accordance with recommendations, although with a potential for improvement in influenza vaccination.
Objective
Infective endocarditis (IE) mimics primary systemic vasculitis, and there are sporadic reports of positivity for antineutrophil cytoplasmic antibodies (ANCAs) among patients with IE. ...Because the frequency of ANCAs in IE is unknown, this study was undertaken to assess the seroprevalence of ANCAs in a large number of patients with IE.
Methods
The study was conducted in the framework of a single‐center prospective cohort study of incident IE cases. Demographic, clinical, laboratory, and microbiologic data were collected, and magnetic resonance imaging of the brain was performed at diagnosis. For those patients whose serum had been stored at diagnosis, ANCAs were assessed by indirect immunofluorescence assay in ethanol‐, formalin‐, and methanol‐fixed neutrophils. In addition, ANCA specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) was assessed by enzyme‐linked immunosorbent assay. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anticardiolipin antibodies (aCL), and serum Ig levels were also measured. Comparisons between groups were made using Wilcoxon's rank sum and chi‐square or Fisher's exact tests.
Results
Among 109 patients with IE, 18% had cytoplasmic ANCAs (cANCA) and/or perinuclear ANCAs (pANCA) and 8% had PR3‐ANCAs or MPO‐ANCAs, some with very high titers. Positivity for both cANCA or pANCA and PR3‐ANCAs or MPO‐ANCAs was found in 6% of patients, and RF, ANAs, and aCL were detected in 35%, 16%, and 23% of samples, respectively. No consistent clinical pattern of IE was observed in the anti‐PR3/anti‐MPO–positive IE patients, whereas positivity for cANCA/pANCA was associated with younger age (P = 0.022), more frequent occurrence of echocardiographic vegetations (P = 0.043), and above‐normal serum IgG levels (P = 0.017).
Conclusion
ANCAs, including PR3‐ and MPO‐ANCAs, occur in a substantial proportion of patients with IE. The link between cANCA/pANCA and specific features of IE requires further study.
Community Acute Bacterial Meningitis (CABM) is a rare infectious disease leading to important impairments. Our aim was to describe CABM survivors' quality of life (QOL) 12 months post-CABM and to ...assess its associations with CABM sequelae.
Patients included in the CABM COMBAT cohort were evaluated one year after the CABM episode. Data were collected by questionnaire, via phone calls with the patients. The WHOQOL-BREF was used to measure CABM survivors' QOL. Hierarchical multivariate linear regressions were performed.
Study population was composed of 284 patients. At 12 months, 53.9% (153/284) reported at least incident headache/worsening headache intensity at 12 months post-CABM, and/or incident hearing impairment, and/or unfavourable disability outcome (GOS). Unfavourable disability outcome was associated with lower physical health QOL (B = -30.35, p<0.001), lower mental health QOL (B = -15.31, p<0.001), lower environmental QOL (B = -11.08, p<0.001) and lower social relationships QOL (B = -9.62, p<0.001). Incident headache/worsening headache since meningitis onset was associated with lower psychological health (B = -5.62, p = 0.010). Incident hearing impairment was associated with lower physical QOL (B = -5.34, p = 0.030). Hierarchical regressions showed that CABM impairments significantly increase explanatory power of multivariate models (for physical health R2 change = 0.42, p<0.001, for psychological health R2 change = 0.23, p<0.001, for social relationships R2 change = 0.06, p<0.001 and for environment domain R2 change was 0.15, p<0.001).
12 month-CABM burden is heavy. Early detection and management of CABM impairments should be performed in clinical practice as early as possible to optimize patients' psychological and psychosocial functioning.
NCT01730690.
Community-acquired bacterial meningitis is a rare but severe central nervous system infection that may be associated with cerebrovascular complications (CVC). Our objective is to assess the ...prevalence of CVC in patients with community-acquired bacterial meningitis and to determine the first-48 h factors associated with CVC.
We analyzed data from the prospective multicenter cohort study (COMBAT) including, between February 2013 and July 2015, adults with community-acquired bacterial meningitis. CVC were defined by the presence of clinical or radiological signs (on cerebral CT or MRI) of focal clinical symptom. Factors associated with CVC were identified by multivariate logistic regression.
CVC occurred in 128 (25.3%) of the 506 patients in the COMBAT cohort (78 (29.4%) of the 265 pneumococcal meningitis, 17 (15.3%) of the 111 meningococcal meningitis, and 29 (24.8%) of the 117 meningitis caused by other bacteria). The proportion of patients receiving adjunctive dexamethasone was not statistically different between patients with and without CVC (p = 0.84). In the multivariate analysis, advanced age (OR = 1.01 1.00-1.03, p = 0.03), altered mental status at admission (OR = 2.23 1.21-4.10, p = 0.01) and seizure during the first 48 h from admission (OR = 1.90 1.01-3.52, p = 0.04) were independently associated with CVC.
CVC were frequent during community-acquired bacterial meningitis and associated with advanced age, altered mental status and seizures occurring within 48 h from admission but not with adjunctive corticosteroids.
Leptospirosis is a major public health concern in New Caledonia (NC) and in other tropical countries. Severe manifestations of the disease are estimated to occur in 5-15% of all human infections ...worldwide and factors associated with these forms are poorly understood. Our objectives were to identify risk factors and predictors of severe forms of leptospirosis in adults.
We conducted a retrospective case-control study of inpatients with laboratory-confirmed leptospirosis who were admitted to two public hospitals in NC in 2008-2011. Cases were patients with fatal or severe leptospirosis, as determined by clinical criteria. This approach was meant to be pragmatic and to reflect the routine medical management of patients. Controls were defined as patients hospitalized for milder leptospirosis. Risk and prognostic factors were identified by multivariate logistic regression. Among the 176 patients enrolled in the study, 71 had criteria of severity including 10 deaths (Case Fatality Rate = 14.1%). Three risk factors were independently associated with severe leptospirosis: current cigarette smoking (OR = 2.94 CI 1.45-5.96); delays >2 days between the onset of symptoms and the initiation of antibiotherapy (OR = 2.78 CI 1.31-5.91); and Leptospira interrogans serogroup Icterohaemorrhagiae as the infecting strain (OR = 2.79 CI 1.26-6.18). The following post-admission laboratory results correlated with poor prognoses: platelet count ≤50,000/µL (OR = 6.36 CI 1.79-22.62), serum creatinine >200 mM (OR = 5.86 CI 1.61-21.27), serum lactate >2.5 mM (OR = 5.14 CI 1.57-16.87), serum amylase >250 UI/L (OR = 4.66 CI 1.39-15.69) and leptospiremia >1000 leptospires/mL (OR = 4.31 CI 1.17-15.92).
To assess the risk of developing severe leptospirosis, our study illustrates the benefit for clinicians to have: i) the identification of the infective strain, ii) a critical threshold of qPCR-determined leptospiremia and iii) early laboratory results. In New Caledonia, preventative measures should focus on early presumptive antibacterial therapy and on rodent (reservoir of Icterohaemorrhagiae serogroup) control.
Determinants of the progression of aortic stenosis (AS) remained unclear. Metabolic syndrome (MetS) and diabetes are suspected to play an active role but literature is scarce and results conflicting. ...We sought to assess their impact in an ongoing prospective cohort of asymptomatic patients with at least mild AS.
We enrolled 203 patients (73±9years, 75% men) with at least 2years of follow-up. Risk-factors assessment was performed at baseline. Annual progression was calculated as (final-baseline measurements)/follow-up duration for both mean pressure gradient (MPG) and degree of aortic valve calcification (AVC) measurements.
Ninety-nine patients (49%) had MetS and 50 (25%) had diabetes (including 39 with MetS). After a mean follow-up of 3.2±1.2years, AS progression was not different between patients with and without MetS either using MPG (+3±3 vs. +4±4mmHg/year, p=0.25) or AVC (+211±231 vs. +225±222AU/year, p=0.75). Same results were obtained for patients with diabetes (3±3 vs. 4±4mmHg/year p=0.53, 187±140 vs. 229±248AU/year p=0.99). MetS had no impact on AS progression in all tested subgroups based on age, statin prescription, valve anatomy and AS severity (all p≥0.10).
In our prospective cohort of AS patients, we found no impact of MetS or diabetes on AS progression. Although MetS and diabetes should be actively treated, no impact on AS progression should be expected. Our results support the theory that if cardiovascular risk-factors may play a role at the early phase of AS disease they have no or limited influence on AS progression.
Intercellular communication within pancreatic ductal adenocarcinoma (PDAC) dramatically contributes to metastatic processes. The underlying mechanisms are poorly understood, resulting in a lack of ...targeted therapy to counteract stromal-induced cancer cell aggressiveness. Here, we investigated whether ion channels, which remain understudied in cancer biology, contribute to intercellular communication in PDAC.
We evaluated the effects of conditioned media from patient-derived cancer-associated fibroblasts (CAFs) on electrical features of pancreatic cancer cells (PCC). The molecular mechanisms were deciphered using a combination of electrophysiology, bioinformatics, molecular and biochemistry techniques in cell lines and human samples. An orthotropic mouse model where CAF and PCC were co-injected was used to evaluate tumour growth and metastasis dissemination. Pharmacological studies were carried out in the Pdx1-Cre, Ink4a
LSL
Kras
(KIC
) mouse model.
We report that the K
channel SK2 expressed in PCC is stimulated by CAF-secreted cues (8.84 vs 2.49 pA/pF) promoting the phosphorylation of the channel through an integrin-epidermal growth factor receptor (EGFR)-AKT (Protein kinase B) axis. SK2 stimulation sets a positive feedback on the signalling pathway, increasing invasiveness in vitro (threefold) and metastasis formation in vivo. The CAF-dependent formation of the signalling hub associating SK2 and AKT requires the sigma-1 receptor chaperone. The pharmacological targeting of Sig-1R abolished CAF-induced activation of SK2, reduced tumour progression and extended the overall survival in mice (11.7 weeks vs 9.5 weeks).
We establish a new paradigm in which an ion channel shifts the activation level of a signalling pathway in response to stromal cues, opening a new therapeutic window targeting the formation of ion channel-dependent signalling hubs.
Influenza vaccine adherence remains low. Communication of virological diagnosis to adults hospitalized with influenza-like illness (ILI) could improve their willingness to be subsequently vaccinated. ...We prospectively assessed, in adults hospitalized with ILI in six French university hospitals, their willingness to be vaccinated against influenza in the subsequent season, both before and after the communication of RT-PCR Influenza laboratory result; we identified then the determinants associated with the willingness to be vaccinated.
A total of 309 patients were included during the 2012-2013 and 2013-2014 influenza seasons; 43.8% reported being vaccinated against influenza for the current season; before communication of influenza laboratory results, 65.1% reported willingness to be vaccinated during the subsequent season. Influenza was virologically confirmed in 103 patients (33.3%). The rate of vaccine willingness increased to 70.4% (p = .02) after communication of influenza laboratory results. Factors independently associated with the willingness to be vaccinated were the perception of influenza vaccine benefits (adjusted relative risk (aRR): 1.06, 95%CI 1.02-1.10), cues to action (aRR: 1.08, 95%CI 1.03-1.12), current season influenza vaccination (aRR: 1.38, 95%CI 1.20-1.59) and communication of a positive influenza laboratory result (aRR: 1.18, 95%CI 1.03-1.34). This last was associated with the willingness to be vaccinated only in the subpopulation of patients not vaccinated (aRR: 1.53, 95%CI 1.19-1.96).
In patients hospitalized with ILI, communication of a positive influenza diagnostic led to a better appreciation of the disease's severity and increased the willingness to be vaccinated. This approach might be particularly beneficial in patients who do not have a history of influenza vaccination.
•An IgG and IgA -mediated humoral response directed against the N and S antigens is detected in the nasopharyngeal swabs of 2 severe COVID-19 patients but not in 2 pauci-symptomatic patients.•Anti-N ...and anti-S serological responses differ according to the disease outcome, with reduced IgG response and enhanced anti-N IgA response in severe patient with fatal disease.•Low serological response occurred in pauci-symptomatic patients, predominated by anti-S antibodies.
The systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, less is known about the mucosal responses in the upper airways, the site of initial SARS-CoV-2 replication.
The IgG and IgA antibody responses were analysed in plasma and nasopharyngeal swabs from the first four confirmed COVID-19 patients in France. Two were pauci-symptomatic while two developed severe disease. We characterized their antibody profiles by using an in-house ELISA to detect antibodies directed against SARS-CoV-2 Nucleoprotein and Spike.
Anti-N IgG and IgA antibodies were detected in the NPS of severe patients only. The levels of antibodies in the plasma markedly differed amongst the patients. The most distinctive features are a strong anti-N IgG response in the severe patient who recovered, and a high anti-N IgA response specifically detected in the fatal case of COVID-19.
Anti-N IgG and IgA antibodies are detected in NPS only for severe patients, with levels related to serological antibodies. The severe patients showed different antibody profiles in the plasma, notably regarding the IgA and IgG response to the N antigen, that may reflect different disease outcome. By contrast, pauci-symptomatic patients did not exhibit any mucosal antibodies in NSP, which is associated with a low or absent serological response against both N and S.
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