Search

Introduction: Respiratory tract disorders are common in children. However, there is no available data on the prescription of respiratory medications for children in France. This study aimed to provide an overview of medications for obstructive airway diseases prescriptions for children during the initial ten years of their lives within POMME, a French population-based cohort of children., Material and Methods: This longitudinal, population-based study used data from the French POMME birth cohort, comprising children born in Haute Garonne between July 2010 and June 2011. Anonymous medical information, including medication reimbursement data, was collected between ages 0 and 10 years. Exposure was defined as at least one prescription for respiratory medications (ATC code R03*), focusing on specific subclasses. Data were analyzed by age, season, and prescribing physicians' specialties., Results: Out of 5956 children, 4951 (83.1 %) received respiratory medication prescriptions. Inhaled corticosteroids (ICSs) were the most prescribed (95.3 %), followed by short-acting β2-agonists (68.8 %). The number of prescriptions increased with age, except for ICSs alone, which peaked between 6 months and 2 years. The average number of prescriptions per child was relatively low., Discussion: This study highlighted high prescription rates of respiratory medications in children under 10 years, with ICSs being the most prevalent. While these medications are primarily intended for asthma management, the findings suggested a significant proportion of off-label prescriptions, especially in young children. Further research and clinical guidance are warranted to ensure appropriate medication use in the pediatric population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Necrotizing pneumonia (NP) is a serious and rare disease in children. Pediatric data on NP are limited and the impact of the 13-valent pneumococcal conjugate vaccine has been very poorly evaluated., Patients and Methods: We conducted a retrospective study at Toulouse University Hospital between 2008 and 2018. Children who presented with thin-walled cavities in the areas of parenchymal consolidation on imaging were included in the study., Results: The incidence of NP did not decrease during this period. Bacterial identification occurred in 56% of cases (14/25) and included six cases of Streptococcus pneumoniae, five of Staphylococcus aureus, two of Streptococcus pyogenes, and one of Streptococcus viridans. Streptococcus pneumoniae NP are more frequently associated with empyema/parapneumonic effusion compared to S. aureus NP (p = 0.02). Patients with S. pyogenes NP more often required volume expansion than did S. pneumoniae cases (p = 0.03). When comparing children born before and after implementation of the 13-valent pneumococcal conjugate vaccine, we identified a relative modification of the bacterial epidemiology, with an increase in the proportion of S. pyogenes NP and S. aureus NP and a decrease in the proportion of NP caused by S. pneumoniae., Conclusion: Future studies are needed to assess the epidemiology of NP in children. Continued surveillance of identified pneumococcal serotypes is essential to document epidemiological changes in the coming years., Competing Interests: Declaration of competing interest none for M. Cathalau, M. Michelet, A. Rancé, G. Martin-Blondel, O. Abbo, D. Dubois, G. Labouret, E. Grouteau, I. Claudet, L. Ricco, L. Roditis, JM. Mansuy, S. Simon, and C. Bréhin, (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background & Aims: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients., Methods: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays., Results: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2., Conclusions: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV., Impact and Implications: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Pegylated-interferon-alpha (Peg-IFNα), an injectable innate immune protein, is still used to treat chronically HBV-infected patients, despite its poor tolerability. Peg-IFNα has the advantage over nucleos(t)ide analogues (NAs) to be administrated in finite regimen and to lead to a higher HBsAg loss rate. Yet it would be interesting to improve the efficacy (i.e. while decreasing doses), or replace, this old medicine by novel small molecules/stimulators able to engage innate immune receptors in both HBV replicating hepatocytes and relevant innate immune cells. We have previously identified the Toll-Like-Receptor (TLR)-2 agonist Pam3CSK4 as such a potential novel immune stimulator. The aim of this study was to gain insights on the antiviral mechanisms of action of this agonist in in vitro cultivated human hepatocytes., Design: We used in vitro models of HBV-infected cells, based on both primary human hepatocytes (PHH) and the non-transformed HepaRG cell line to investigate the MoA of Pam3SCK4 and identify relevant combinations with other approved or investigational drugs., Results: We exhaustively described the inhibitory anti-HBV phenotypes induced by Pam3CSK4, which include a strong decrease in HBV RNA production (inhibition of synthesis and acceleration of decay) and cccDNA levels. We confirmed the long-lasting anti-HBV activity of this agonist, better described the kinetics of antiviral events, and demonstrated the specificity of action through the TLR1/2- NF-κB canonical-pathway. Moreover, we found that FEN-1 could be involved in the regulation and inhibitory phenotype on cccDNA levels. Finally, we identified the combination of Pam3CSK4 with IFNα or an investigational kinase inhibitor (called 1C8) as valuable strategies to reduce cccDNA levels and obtain a long-lasting anti-HBV effect in vitro., Conclusions: TLR2 agonists represent possible assets to improve the rate of HBV cure in patients. Further evaluations, including regulatory toxicity studies, are warranted to move toward clinical trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Aims: To assess the diagnostic and therapeutic difficulties as well as the long-term complications of prolonged endobronchial foreign body retention., Method: Between January 2000 and May 2021, 794 patients with suspected foreign body aspiration (FBA) were hospitalized in our department. A total of 12 patients with a delayed diagnosis of over 1 month were included. FBAs were confirmed by flexible or rigid endoscopy. A retrospective analysis of medical records was performed., Results: Six male patients and six female patients were hospitalized due to prolonged FBA. The average age was 6.90 years (range: 1-13 years). The average duration of the foreign body retention was 2.60 years (2 months to 9 years). A choking event was found in eight cases. Coughing and wheezing were the main symptoms and signs. A misdiagnosis of asthma was made for five patients. Two atypical clinical presentations led to diagnosis of endobronchial foreign body, unilateral pleurisy, and hemoptysis. We report one case of an occult foreign body externalized spontaneously through a pneumo-pleuro-cutaneous fistula. The most common clinical and radiological findings were of pneumonia and atelectasis. Computed tomography showed localized bronchiectasis in three patients. FBAs were removed with a rigid bronchoscope in eight cases. Other extractions were carried out with a flexible endoscope. The foreign bodies were most frequently of vegetable origin, such as seeds and peanuts. A granulation tissue was observed in seven cases. Bronchial stenosis and bronchiectasis are the most common late complications. Only one patient needed a surgical intervention., Conclusions: FBA should always be considered in the differential diagnosis of chronic or recurrent respiratory diseases, even in the absence of a previous choking event. Clinical and radiological findings should be carefully evaluated for a possible FBA. Delay in diagnosis and treatment of FBA should be avoided in order to prevent complications. Open surgery may be required when lung abscess has occurred., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2022. Published by Elsevier Masson SAS. All rights reserved.)

Background & Aims: Over time, chronic HCV infection can lead to hepatocellular carcinoma (HCC), a process that involves changes to the liver extracellular matrix (ECM). However, the exact mechanisms by which HCV induces HCC remain unclear. Therefore, we sought to investigate the impact of HCV on the liver ECM, with a focus on heparanase-1 (HPSE)., Methods: HPSE expression was assessed by quantitative reverse-transcription PCR, immunoblotting and immunofluorescence in liver biopsies infected or not with HCV, and in 10-day-infected hepatoma Huh7.5 cells. Cell lines deficient for or overexpressing HPSE were established to study its role during infection., Results: HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. Conversely, when HPSE expression was downregulated or its activity blocked, HCV infection dropped, suggesting a role of HPSE in the HCV life cycle. We further studied the underlying mechanisms of such observations and found that HPSE favored HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. We also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation., Conclusions: We report for the first time that HCV infection is favored by HPSE, and upregulates HPSE expression and secretion, which may result in pathogenic alterations of the ECM., Lay Summary: Chronic hepatitis C virus (HCV) infection can lead to hepatocellular carcinoma development in a process that involves derangement of the extracellular matrix (ECM). Herein, we show that heparanase-1, a protein involved in ECM degradation and remodeling, favors HCV infection and is upregulated by HCV infection; this upregulation may result in pathogenic alterations of the ECM., Competing Interests: Conflict of interest The authors declareno conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic hepatitis D is the most severe form of chronic viral hepatitis and to date, efficient therapeutic approaches against hepatitis D virus (HDV) are limited. Among the antiviral molecules currently tested in clinical trials, the farnesyl transferase inhibitor (FTI) Lonafarnib inhibits the prenylation of the large delta antigen (L-HDAg), blocking virus assembly. Given the importance of L-HDAg in the virus life cycle, we hypothesized that Lonafarnib treatment may have side effects on virus replication. Here, we setup an innovative method for the quantification of HDV RNA allowing the independent quantification of edited and non-edited versions of the HDV genome upon infection. We demonstrated that FTI treatment of HBV/HDV co-infected dHepaRG or primary human hepatocytes leads to an accumulation of intracellular HDV RNAs and a marked increase in the levels of edited RNAs non only within the infected cells but also in the viral particles that are produced. Interestingly, these viral particles were less infectious, probably due to an enrichment in edited genomes that are packaged, leading to unproductive infection given the absence of S-HDAg synthesis after viral entry. Taken together, we setup an innovative quantification method allowing the investigation of RNA editing during HDV infection in a simple, fast, clinically-relevant assay and demonstrated for the first time the dual antiviral activity of FTI on HDV infection., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This exploratory study aimed at investigating profiles of care needs in people with mild to moderate dementia and examined variables associated with these profiles., Design: A longitudinal international cohort study., Setting and Participants: The baseline data of 447 community-dwelling dyads of people with dementia and their caregivers from the Access to Timely Formal Care (Actifcare) Study were included for analysis., Methods: A latent class analysis was applied to identify profiles of needs, measured with the Camberwell Assessment of Need for the Elderly as rated by the caregiver. We examined sociodemographic (eg, relative stress scale) and clinical characteristics (eg, neuropsychiatric inventory) associated with these profiles., Results: Four distinct need profiles were identified through latent class analysis. These comprised a "no need" profile (41% of the sample), a "met psychological needs" profile (25%), a "met social needs" profile (19%), and an "unmet social needs" profile (15%). A larger impact of caregiving on the caregiver's life as indicated by a higher relative stress scale score was associated with the "unmet social needs" profile., Conclusions and Implications: In this large European sample, there was a subgroup of persons with dementia with high "unmet social needs" whose caregivers simultaneously perceived high stress in their caregiving tasks. Identification of these profiles may help provision of appropriate support for these people., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Cardiac arrhythmia with sudden death is rare in children but mainly due to ventricular tachycardia. In case of pulseless ventricular tachycardia, prehospital treatment is crucial with immediate cardiopulmonary resuscitation and external electrical cardioversion. We report the case of pulseless ventricular tachycardia in a child with no past medical history. Sinus rhythm was obtained after 12min of cardiorespiratory resuscitation and three external electrical shocks. An exhaustive diagnostic approach allow us to find its origin. The clinical progression was marked by a severe encephalopathy. The authors discuss different etiologies and treatment of arrhythmia in children, reviewing the pediatric algorithm for shockable rhythm., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Hepatitis B Virus (HBV) persists in infected hepatocytes as an episomal covalently-closed-circular DNA mini-chromosome, called cccDNA. As the main nuclear transcription template, HBV cccDNA is a key replication intermediate in the viral life cycle. Little is known about the mechanisms involved in its formation, maintenance and fate under antiviral therapies. This is mainly due to the lack of small immune-competent animal models able to recapitulate the entire HBV replication cycle, including formation of HBV cccDNA. Here we report that HBV cccDNA can be detected by Southern blot analyses in the liver of C57BL6 mice transduced with AAV-HBV. HBV cccDNA persists in the liver of these animals together with the AAV-HBV episome. We also set up a PCR strategy to distinguish the HBV cccDNA from the AAV-HBV episome. These suggest that the AAV-HBV/mouse model might be relevant to test drugs targeting HBV cccDNA regulation and persistence., (Copyright © 2017. Published by Elsevier B.V.)

Hepatitis D virus (HDV) super-infection of Hepatitis B virus (HBV)-infected patients is the most aggressive form of viral hepatitis. HDV infection is not susceptible to direct anti-HBV drugs, and only suboptimal antiviral responses are obtained with interferon (IFN)-alpha-based therapy. To get insights on HDV replication and interplay with HBV in physiologically relevant hepatocytes, differentiated HepaRG (dHepaRG) cells, previously infected or not with HBV, were infected with HDV, and viral markers were extensively analyzed. Innate and IFN responses to HDV were monitored by measuring pro-inflammatory and interferon-stimulated gene (ISG) expression. Both mono- and super-infected dHepaRG cells supported a strong HDV intracellular replication, which was accompanied by a strong secretion of infectious HDV virions only in the super-infection setting and despite the low number of co-infected cells. Upon HDV super-infection, HBV replication markers including HBeAg, total HBV-DNA and pregenomic RNA were significantly decreased, confirming the interference of HDV on HBV. Yet, no decrease of circular covalently closed HBV DNA (cccDNA) and HBsAg levels was evidenced. At the peak of HDV-RNA accumulation and onset of interference on HBV replication, a strong type-I IFN response was observed, with interferon stimulated genes, RSAD2 (Viperin) and IFI78 (MxA) being highly induced. We established a cellular model to characterize in more detail the direct interference of HBV and HDV, and the indirect interplay between the two viruses via innate immune responses. This model will be instrumental to assess molecular and immunological mechanisms of this viral interference., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background & Aims: The outcome of hepatitis B virus (HBV) infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated., Methods: We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24h of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon stimulated genes. Experiments were also performed in the presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses., Results: We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on Toll-like receptor 3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication., Conclusions: Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: HepaRG cells are considered as the best surrogate model to primary human hepatocyte (PHH) culture to investigate host-pathogen interactions. Yet their innate immune functions remain unknown. In this study, we explored the expression and functionality of Toll-like (TLR) and retinoic acid-inducible gene-1 (RIG-I)-like receptors (RLR) in these cells., Methods: Gene and protein expression levels of TLR-1 to 9 and RLR in HepaRG were mainly compared to PHH, by RT-qPCR, FACS, and Western blotting. Their functionality was assessed, by measuring the induction of toll/rig-like themselves and several target innate gene expressions, as well as the secretion of IL-6, IP-10, and type I interferon (IFN), upon agonist stimulation. Their functionality was also shown by measuring the antiviral activity of some TLR/RLR agonists against hepatitis B virus (HBV) infection., Results: The basal gene and protein expression profile of TLR/RLR in HepaRG cells was similar to PHH. Most receptors, except for TLR-7 and 9, were expressed as proteins and functionally active as shown by the induction of some innate genes, as well as by the secretion of IL-6 and IP-10, upon agonist stimulation. The highest levels of IL-6 and IP-10 secretion were obtained by TLR-2 and TLR-3 agonist stimulation respectively. The highest preventive anti-HBV activity was obtained following TLR-2, TLR-4 or RIG-I/MDA-5 stimulations, which correlated with their high capacity to produce both cytokines., Conclusions: Our results indicate that HepaRG cells express a similar pattern of functional TLR/RLR as compared to PHH, thus qualifying HepaRG cells as a surrogate model to study pathogen interactions within a hepatocyte innate system., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to increase disease-free survival (DFS) in AML in CR1 using a high-dose cytarabine consolidation plus G-CSF as in vivo purging and mobilization of CD34+ cells before ablative therapy and peripheral blood autograft., Patients and Methods: Fifty-six consecutive AML patients (pts) (including 11 children < 15 years), with a median age of 32 years, were analyzed. After achievement of CR with cytarabine-mitoxantrone (7 + 3) in adults and a BFM-like protocol in children, pts were intensified with cytarabine 2 g/m2 x six doses plus mitoxantrone for adults, or, 3 g/m2 x six doses plus etoposide for children, followed by G-CSF 5 micrograms/kg SC daily. The ablative regimens used were busulfan and cyclophosphamide (Bu/Cy) in standard-risk pts plus etoposide (2400 mg/m2) for high-risk pts., Results: For the 54 pts who underwent autologous transplant, the median time to reach > 1.0 x 10(9)/l neutrophils was 13 days (8-48), and to reach platelets > 25 x 10(9)/l 32 days (8-364), and the median numbers of red blood cell and platelet units transfused were 3 and 5, respectively. Six pts had treatment-related deaths (11%). The disease-free survival and overall survival at 30 months (mos) for the 56 eligible pts were 61% and 62%, respectively. Only two relapses were observed after 21 mos, while there were 12 relapses within 12 mos., Conclusions: The above treatment results in a similar DFS rate as does rescue with bone marrow cells, with faster neutrophil and platelet recovery.