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Background: Diagnosis of allergies is mostly based on the patient's clinical history and allergen provocation tests. Determination of specific IgE (sIgE) profiles can be performed to support allergy diagnosis. This is commonly done in vivo by the skin prick test or in vitro with automated systems. Several platforms exist to quantify sIgE levels, but all these methods require access to specific instruments, often delaying the test's results. The IgE luciferase-linked immunosorbent assay (LuLISA) allows bioluminescent quantification of IgE against peanut in microliter samples, but this method awaits extension to other allergens. This study aimed to validate a new method, named LuLIPLEX, for multiplexed bioluminescent detection of sIgE against 20 major molecular allergens., Methods: Quantification of sIgE against 12 recombinant or purified food allergens and eight aeroallergens was performed by LuLIPLEX versus standard IgE detection methods (ImmunoCAP, ISAC, ALEX, or NOVEOS). Multiplexed detection of IgE against these 20 allergens was performed within 45 min using 50 μL of serum, plasma, or whole blood samples., Results: A head-to-head comparison between LuLIPLEX and standard IgE detection methods showed a high correlation among all allergens tested. sIgE profiles in polysensitized subjects could be determined within 45 min in serum and plasma samples, as well as using a single drop of capillary blood., Conclusions: LuLIPLEX is a rapid and sensitive method to quantify sIgE levels against multiple allergens. Given that the test is very fast and can be performed on small and inexpensive luminometers, the IgE LuLIPLEX could allow point-of-care testing of sIgE profiles in allergic subjects., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objective: Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment., Design: We identified TLR8 -expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN's indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN's effect were validated using transcriptomic data from HBV-infected patients., Results: Hepatic TLR8 expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg, S100A12 ) and downregulated genes associated with the KC identity (eg, SPIC ). Treatment of hepatocytes with SLGN-CM downregulated NTCP and impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition., Conclusion: Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection., Competing Interests: Competing interests: FZ and BT received grants from Assembly, Beam Therapeutics, Blue Jay and JnJ; FZ had consulting activities with Assembly, Blue Jay and GSK. YCH receives grants from Gilead Sciences and Sysmex. FZ is an associate editor of the journal. SD, LL, NK, JJW, AHL, and SPF are or were employees of Gilead Sc., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

The liver microenvironment contains a wide variety of monocyte and macrophage populations. Here, we present a protocol for the specific isolation of liver-resident macrophages, known as Kupffer cells (KCs), from human liver resections. We describe steps for dissociating human liver tissues, separating non-parenchymal cells into fractions by a 2-phase iodixanol gradient, and positive selection of KCs based on the expression of CD163. We then provide instructions for validating the procedure by immunofluorescence to detect CD163. For complete details on the use and execution of this protocol, please refer to Roca Suarez, Plissonnier, et al. 1 ., Competing Interests: Declaration of interests This work was performed as a scientific collaboration with Gilead Sciences, who provided the TLR8 agonist SLGN, in the frame of the EU-funded IP-cure-B project., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.)

Introduction: Extreme obesity (BMI ≥50 kg/m2) is a complex pathology to treat. One of the complications of extreme obesity is massive localized lymphedema (MLL), due to compromised lymphatic drainage. There is a lack of literature guiding the medical management of these conditions., Case Presentation: We present a 43-year-old male who was admitted to our specialized obesity center for weight management. His initial weight was 255 kg and BMI was 93.7 kg/m2. He suffered from massive multifocal lymphedema of his left leg. He was bedridden due to his condition and malnourished, as shown by multiple vitamin deficiencies. The patient received care from our multidisciplinary team including nurses, dieticians, physical therapists, and psychologists. Treatment with semaglutide was started in hospital and continued at home. The maximal dose used was 1 mg/week but decreased during follow-up to 0.25 mg/week to avoid malnutrition. Protein and nutritional supplements were added. At 28 weeks of therapy, the patient had lost 40 kg or 15.7% of his total body weight. His lymphedema decreased; he had lost at least 16 cm of his left thigh circumference. He was able to walk again and regain autonomy of his daily activities of living., Conclusion: Semaglutide can be effective in patients with extreme obesity, with the support of a multidisciplinary team in a specialized obesity center. It can also help decrease MLL. More data are needed to guide medical treatment of patients with extreme obesity and MLL., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: The clinical significance of newly available platforms for specific IgE measurement must be evaluated. However, data are lacking for NOVEOS (Hycor), especially for food allergens., Objective: We compared the technical and clinical performance of two platforms (ImmunoCAP and NOVEOS) to measure specific IgE to 10 food allergens., Methods: Sera from 289 clinically characterized patients were tested for IgE specific for six food allergen extracts (egg white, cow's milk, peanut, hazelnut, fish, and shrimp) and four molecular allergens (Gal d 1, Bos d 8, Ara h 2, and Cor a 14). Specific IgE measurements were carried out using ImmunoCAP and NOVEOS methods. Food allergy diagnoses were established according to international guidelines., Results: A strong correlation (ρ > 0.9) was present between the two platforms whereas specific IgE concentrations measured with NOVEOS were consistently lower (mean, -15%) than with ImmunoCAP. NOVEOS and ImmunoCAP provided similar overall odds ratios and relative risks for food allergy diagnosis with both allergen extracts and molecular allergens. When all 10 allergens were considered, NOVEOS provided better receiver operating characteristic curves (P = .04). Finally, we found that the most discordant results were observed with hazelnut and peanut extracts and were related to cross-reactive carbohydrate determinants for these two with ImmunoCAP., Conclusions: Specific IgE determination by either ImmunoCAP or NOVEOS (odds ratios of allergy, 25.1 or 33.0, respectively) is highly informative regarding the risk of allergy in the selected population. The NOVEOS platform presents the advantage of being less affected by unwanted reactivity owing to carbohydrate determinant-specific IgE while requiring a 10-fold lower test sample volume., (Copyright © 2024 The Authors. Published by Elsevier Inc. 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.)

Phase separation regulates fundamental processes in gene expression and is mediated by the local concentration of proteins and nucleic acids, as well as nucleic acid secondary structures such as G-quadruplexes (G4s). These structures play fundamental roles in both host gene expression and in viral replication due to their peculiar localisation in regulatory sequences. Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is an episomal minichromosome whose persistence is at the basis of chronic infection. Identifying the mechanisms controlling its transcriptional activity is indispensable to develop new therapeutic strategies against chronic hepatitis B. The aim of this study was to determine whether G4s are formed in cccDNA and regulate viral replication. Combining biochemistry and functional studies, we demonstrate that cccDNA indeed contains ten G4s structures. Furthermore, mutations disrupting two G4s located in the enhancer I HBV regulatory region altered cccDNA transcription and viral replication. Finally, we showed for the first time that cccDNA undergoes phase separation in a G4-dependent manner to promote its transcription in infected hepatocytes. Altogether, our data give new insight in the transcriptional regulation of the HBV minichromosome that might pave the way for the identification of novel targets to destabilize or silence cccDNA., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Life expectancy (LE) is increasing worldwide, while there is lack of information on how this affects older individuals' use of formal home care services., Aim: We aimed to decompose LE into years with and without home care services and estimate projected number of users towards 2050 in Norway for people 70 years or older., Methods: This study is based on a sample of 25,536 participants aged 70 years and older in the Trøndelag Health Study (HUNT) survey 2 (1995-1997), 3 (2006-2008), or 4 (2017-2019) linked with national data on mortality. Prevalence of home care services was standardised to the Norwegian population by age and sex. The Sullivan method was used to estimate expected years with and without home help services and nursing services for the years 1995, 2006 and 2016. Data from HUNT4 and Statistics Norway were used to estimate projected use of these services between 2020 and 2050., Results: During 1995-2017, the use of home help services decreased from 22.6% to 6.2% (p < 0.001), and from 6.4% to 5.5% (p = 0.004) for home nursing services. Adjusted for age and sex, the use of home help services decreased significantly over time (p < 0.001), while home nursing services were stable (p = 0.69). LE at age 70 increased from 11.9 to 15.3 years in men (p < 0.05) during 1995-2017, and from 14.7 to 17.1 in women (p < 0.05). In the same period, the expected years receiving home help decreased from 2.6 to 1.1 in men (p < 0.05), and from 4.4 to 2.1 in women (p < 0.05). The expected years receiving home nursing increased from 0.6 to 0.9 in men (p < 0.05), and from 1.3 to 1.7 in women (p < 0.05). Projected numbers of people 70+ in Norway in need of either of these services were estimated to rise from 64,000 in 2020 to 160,000 in 2050., Conclusion: While overall life expectancy increased, the expected years receiving home help have decreased and home nursing slightly increased among the Norwegian population aged 70 years and older during 1995-2017. However, the substantial increase in the projected number of older adults using home care services in the future is an alert for the current health care planners., (© 2023 Nordic College of Caring Science.)

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.)

Background and Aims: HDV, a satellite of HBV, is responsible for the most severe form of human viral hepatitis, for which curative therapy is still awaited. Both HBV and HDV use the hepatic transporter of bile acids (ie, Na+-taurocholate cotransporting polypeptide) to enter hepatocytes. We have previously shown that ligands of the farnesoid-X-receptor alpha (FXR), a master regulator of bile acids metabolism, inhibit HBV replication. Here we asked whether FXR ligands can also control HDV infection., Approach and Results: In vitro HDV monoinfections or HDV/HBV coinfections and superinfections were performed in differentiated HepaRG cells (dHepaRG) and primary human hepatocytes. Following treatment with FXR ligands, HDV RNAs and antigens were analyzed by RT-qPCR, northern blot, immunofluorescence, and western blot. Virus secretion was studied by RNA quantification in supernatants, and the infectivity of secreted HDV particles was measured by reinfection of naive HuH7.5-Na+-taurocholate cotransporting polypeptide cells. In HDV/HBV superinfection models, a 10-day treatment with FXR ligand GW4064 decreased intracellular HDV RNAs by 60% and 40% in dHepaRG cells and primary human hepatocytes, respectively. Both HDV genomic and antigenomic RNAs were affected by treatment, which also reduced the amount of intracellular delta antigen. This antiviral effect was also observed in HDV monoinfected dHepaRG cells, abolished by FXR loss of function, and reproduced with other FXR ligands. In HBV/HDV coinfected dHepaRG cells, HDV secretion was decreased by 60% and virion-specific infectivity by >95%., Conclusions: FXR ligands both inhibit directly (ie, independently of anti-HBV activity) and indirectly (ie, dependently of anti-HBV activity) the replication, secretion, and infectivity of HDV. The overall anti-HDV activity was superior to that obtained with interferon-α, highlighting the therapeutic potential of FXR ligands in HDV-infected patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Rationale: Children with preschool wheezing represent a very heterogeneous population with wide variability regarding their clinical, inflammatory, obstructive, and/or remodeling patterns. We hypothesized that assessing bronchial remodeling would help clinicians to better characterize severe preschool wheezers. Objectives: The main objective was to identify bronchial remodeling-based latent classes of severe preschool wheezers. Secondary objectives were to compare cross-sectional and longitudinal clinical and biological data between classes and to assess the safety of bronchoscopy. Methods: This double-center prospective study (NCT02806466) included severe preschool wheezers (1-5 yr old) requiring fiberoptic bronchoscopy. Bronchial remodeling parameters (i.e., epithelial integrity, reticular basement membrane [RBM] thickness, mucus gland, fibrosis and bronchial smooth muscle [BSM] areas, the density of blood vessels, and RBM-BSM distance) were assessed and evaluated by latent class analysis. An independent cohort of severe preschool wheezers (NCT04558671) was used to validate our results. Measurements and Main Results: Fiberoptic bronchoscopy procedures were well tolerated. A two-class model was identified: Class BR1 was characterized by increased RBM thickness, normalized BSM area, the density of blood vessels, decreased mucus gland area, fibrosis, and RBM-BSM distance compared with Class BR2. No significant differences were found between classes in the year before fiberoptic bronchoscopy. By contrast, Class BR1 was associated with a shorter time to first exacerbation and an increased risk of both frequent (3 or more) and severe exacerbations during the year after bronchoscopy in the two cohorts. Conclusions: Assessing bronchial remodeling identified severe preschool wheezers at risk of frequent and severe subsequent exacerbations with a favorable benefit to risk ratio.

Background and Aims: Netrin-1 displays protumoral properties, though the pathological contexts and processes involved in its induction remain understudied. The liver is a major model of inflammation-associated cancer development, leading to HCC., Approach and Results: A panel of cell biology and biochemistry approaches (reverse transcription quantitative polymerase chain reaction, reporter assays, run-on, polysome fractionation, cross linking immunoprecipitation, filter binding assay, subcellular fractionation, western blotting, immunoprecipitation, stable isotope labeling by amino acids in cell culture) on in vitro-grown primary hepatocytes, human liver cell lines, mouse samples and clinical samples was used. We identify netrin-1 as a hepatic inflammation-inducible factor and decipher its mode of activation through an exhaustive eliminative approach. We show that netrin-1 up-regulation relies on a hitherto unknown mode of induction, namely its exclusive translational activation. This process includes the transfer of NTN1 (netrin-1) mRNA to the endoplasmic reticulum and the direct interaction between the Staufen-1 protein and this transcript as well as netrin-1 mobilization from its cell-bound form. Finally, we explore the impact of a phase 2 clinical trial-tested humanized anti-netrin-1 antibody (NP137) in two distinct, toll-like receptor (TLR) 2/TLR3/TLR6-dependent, hepatic inflammatory mouse settings. We observe a clear anti-inflammatory activity indicating the proinflammatory impact of netrin-1 on several chemokines and Ly6C+ macrophages., Conclusions: These results identify netrin-1 as an inflammation-inducible factor in the liver through an atypical mechanism as well as its contribution to hepatic inflammation., (© 2022 American Association for the Study of Liver Diseases.)

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.)

Objectives: To examine prospectively the association between unmet needs for daytime activities and company and behavioural and psychological symptoms of dementia., Methods: We included 451 people with mild or moderate dementia, from eight European countries, who were assessed three times over 12 months. Unmet needs were measured with the Camberwell Assessment of Need for the Elderly. Three sub-syndromes of the Neuropsychiatric Inventory-Questionnaire were regressed, one-by-one, against unmet needs for daytime activities and company, adjusting for demographic and clinical-functional covariates., Results: Unmet needs for daytime activities were associated with more affective symptoms at baseline, six and twelve months, mean 0.74 ( p  < 0.001), 0.76 ( p  < 0.001) and 0.78 ( p  = 0.001) points higher score respectively, and with more psychotic symptoms at baseline (mean 0.39 points, p  = 0.007) and at six months follow-up (mean 0.31 points, p  = 0.006). Unmet needs for company were associated with more affective symptoms at baseline, six and twelve months, mean 0.44 ( p  = 0.033), 0.67 ( p  < 0.001) and 0.91 ( p  < 0.001) points higher score respectively, and with more psychotic symptoms at baseline (mean 0.40 points, p  = 0.005) and at six months (mean 0.35 points, p  = 0.002) follow-up., Conclusion: Interventions to reduce unmet needs for daytime activities and company could reduce affective and psychotic symptoms in people with dementia.

Background: Voltage-gated calcium (Ca v 1) channels contribute to T-lymphocyte activation. Ca v 1.2 and Ca v 1.3 channels are expressed in Th2 cells but their respective roles are unknown, which is investigated herein., Methods: We generated mice deleted for Ca v 1.2 in T cells or Ca v 1.3 and analyzed TCR-driven signaling. In this line, we developed original fast calcium imaging to measure early elementary calcium events (ECE). We also tested the impact of Ca v 1.2 or Ca v 1.3 deletion in models of type 2 airway inflammation. Finally, we checked whether the expression of both Ca v 1.2 and Ca v 1.3 in T cells from asthmatic children correlates with Th2-cytokine expression., Results: We demonstrated non-redundant and synergistic functions of Ca v 1.2 and Ca v 1.3 in Th2 cells. Indeed, the deficiency of only one channel in Th2 cells triggers TCR-driven hyporesponsiveness with weakened tyrosine phosphorylation profile, a strong decrease in initial ECE and subsequent reduction in the global calcium response. Moreover, Ca v 1.3 has a particular role in calcium homeostasis. In accordance with the singular roles of Ca v 1.2 and Ca v 1.3 in Th2 cells, deficiency in either one of these channels was sufficient to inhibit cardinal features of type 2 airway inflammation. Furthermore, Ca v 1.2 and Ca v 1.3 must be co-expressed within the same CD4 + T cell to trigger allergic airway inflammation. Accordingly with the concerted roles of Ca v 1.2 and Ca v 1.3, the expression of both channels by activated CD4 + T cells from asthmatic children was associated with increased Th2-cytokine transcription., Conclusions: Thus, Ca v 1.2 and Ca v 1.3 act as a duo, and targeting only one of these channels would be efficient in allergy treatment., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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.)

Immunoglobulin E (IgE)-mediated food allergy is a real public health problem worldwide. The prevalence of food allergy is particularly high in children. Patients with food allergy experience high morbidity with a change in quality of life due to the risk of severe anaphylaxis. Current treatment options are poor. Allergen avoidance is widely recommended but exposes patients to accidental ingestion. Oral immunotherapy is also used in patients with food allergies to the most common allergens. Oral immunotherapy consists of a daily administration of small, gradually increasing amounts of allergens to induce desensitisation. This procedure aims at inducing immune tolerance to the ingested food allergens. However, some patients experience adverse reactions and discontinue oral immunotherapy.Given that IgE plays a crucial role in food allergy and anti-IgE are effective in allergic asthma, the use of anti-IgE therapeutic monoclonal antibodies (mAbs) such as omalizumab has been assessed in food allergy patients. The use of omalizumab as a monotherapy in food allergy has not been extensively studied but looks promising. There is more published evidence regarding the effect of omalizumab and oral immunotherapy in food allergy. Given the promising results of oral immunotherapy regarding sustained tolerance in clinical trials and the potential capacity of omalizumab to reduce symptoms in case of accidental exposure, a strategy combining oral immunotherapy with omalizumab pre-treatment has been suggested as a safer option in patients with severe food allergy compared to isolated therapy. Omalizumab seems useful in ensuring safer administration of oral immunotherapy with the oral immunotherapy maintenance dose being reached more rapidly. Quality-of-life improvement is greater with oral immunotherapy + omalizumab compared to oral immunotherapy alone. Moreover, sustained unresponsiveness is achieved more frequently with omalizumab. Considering that precision medicine and personalised therapy are major goals for allergic diseases, predictive biomarkers are crucial in order to identify food allergy patients more likely to benefit from anti-IgE therapies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)