Study protocol of a prospective, interventional non-randomised trial investigating the impact of asthma education on specific disease understanding, health literacy and therapy outcome in childhood.

INTRODUCTION: Childhood asthma is a highly prevalent chronic disease. A failure to implement patient education programmes may result in increased morbidity, despite the availability of distinct diagnostic and therapeutic approaches. Patients with lower socioeconomic status (SES) tend to have a higher asthma prevalence. Moreover, the progression of asthma is significantly influenced by factors such as health literacy and the children's specific knowledge about the condition. With this trial, the primary objective is to evaluate whether asthma education enhances specific disease understanding in children with asthma (primary outcome). Secondary objectives include evaluating training effects on health literacy, retention rates of information, 'Children Asthma Control Test' (C-ACT) score, frequency of emergency room and physician visits (secondary outcomes) and whether SES influences training effects. METHODS AND ANALYSIS: To address the research objectives, this study comprises two projects. The first subproject will investigate the influence of asthma training on the development of disease understanding and health literacy. The second subproject will analyse the influence of SES on the outcome of children participating in asthma training. This research is designed as a comparative, non-randomised study involving two paediatric groups between the ages of ≥7 and < 14 years. After being diagnosed with asthma, the intervention group undergoes standardised psychoeducational asthma training at a certified centre associated with paediatricians in private practice in Germany, following the recommendations of the 'Arbeitsgruppe Asthmaschulung im Kindes- und Jugendalter e.V.', a national association aiming to establish uniform and guideline-based standards for patient education in children and adolescents. The comparison group receives a significantly shorter period of education and instruction on the usage of asthma medication at outpatient clinics. Data will be collected from patients and their parents at three specific survey time points, based on standardised tools.To describe mean differences between the intervention and control group over time (subproject 1), a repeated-measures analysis of variance (ANOVA) will be conducted. In subproject 2, multivariate linear regression analysis will be used to analyse the variables determining the changes in specific disease understanding and health literacy, including SES. The sample size calculation is based on a mixed ANOVA model with two groups and two measurements resulting in a total of 126 participants. ETHICS AND DISSEMINATION: All protocols and a positive ethics approval were obtained from the Witten/Herdecke University, Germany (S-159, 2023; application submission: 24 June 2023, final vote: 10 July 2023). Furthermore, the study was registered at the German Clinical Trials Register (DRKS), DRKS00032423. The application submission was on 3 August 2023, and the final approval was on 4 August 2023. The results will be disseminated among experts and participants and will be published in peer-reviewed, international journal with open access. TRIAL REGISTRATION NUMBER: DRKS00032423.

Advances of Recombinant Adenoviral Vectors in Preclinical and Clinical Applications.

Adenoviruses (Ad) have the potential to induce severe infections in vulnerable patient groups. Therefore, understanding Ad biology and antiviral processes is important to comprehend the signaling cascades during an infection and to initiate appropriate diagnostic and therapeutic interventions. In addition, Ad vector-based vaccines have revealed significant potential in generating robust immune protection and recombinant Ad vectors facilitate efficient gene transfer to treat genetic diseases and are used as oncolytic viruses to treat cancer. Continuous improvements in gene delivery capacity, coupled with advancements in production methods, have enabled widespread application in cancer therapy, vaccine development, and gene therapy on a large scale. This review provides a comprehensive overview of the virus biology, and several aspects of recombinant Ad vectors, as well as the development of Ad vector, are discussed. Moreover, we focus on those Ads that were used in preclinical and clinical applications including regenerative medicine, vaccine development, genome engineering, treatment of genetic diseases, and virotherapy in tumor treatment.

Transforming Growth Factor ß1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis.

BACKGROUND: High TGFß1-producing variants cause severe clinical disease in F508del homozygous patients. Lately, we showed that a single nucleotide polymorphism (SNP), rs41266431, in the GJA4 gene modifies the disease severity of cystic fibrosis (CF). Our aim was to investigate whether the clinical phenotype associated with GJA4 variants was independent of TGFß1 variants. METHODS: Homozygous F508del patients (n = 115, mean age 27.2 years, m/f (65/50)) were included in this study. A deep sequence analysis was performed for GJA4 and TGBß1, and disease severity was assessed over 3 years using lung function tests (LFTs), body mass index, diabetes mellitus, colonization with Pseudomonas aeruginosa, survival to end-stage lung disease (ESLD), as well as distinct inflammatory biomarkers. RESULTS: The analyses revealed that one SNP (rs41266431) in GJA4 may be clinically relevant. Carriers homozygous for the G variant (n = 84; 73%) presented with worse LFTs (forced vital capacity (FVC) % predicted: mean 80/86.6, p < 0.035) and a lower survival to ESLD (p < 0.029). For the TGBß1 variant: 509 carriers of the C variant (CT + CC genotype, n = 105, 91.3%) had better LFTs (Forced expiratory flow at 75% of the FVC (FEF75% predicted: median 40/29.5, p < 0.015), although a similar outcome to ESLD. A gene-gene interaction was not observed between TGBß1 and GJA4 variants for any clinical measure. CONCLUSIONS: GJA4 variants are independent of TGBß1 variants. Both variants had an impact on the LFTs, although only GJA4 variants were associated with an improved outcome for ESLD. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.

Uncovering the gastrointestinal passage, intestinal epithelial cellular uptake, and AGO2 loading of milk miRNAs in neonates using xenomiRs as tracers.

BACKGROUND: Human breast milk has a high microRNA (miRNA) content. It remains unknown whether and how milk miRNAs might affect intestinal gene regulation and homeostasis of the developing microbiome after initiating enteral nutrition. However, this requires that relevant milk miRNA amounts survive the gastrointestinal (GI) passage, are taken up by cells, and become available to the RNA interference machinery. It seems important to dissect the fate of these miRNAs after oral ingestion and GI passage. OBJECTIVES: Our goal was to analyze the potential transmissibility of milk miRNAs via the gastrointestinal system in neonate humans and a porcine model in vivo to contribute to the discussion of whether milk miRNAs could influence gene regulation in neonates and thus might vertically transmit developmental relevant signals. METHODS: We performed cross-species profiling of miRNAs via deep sequencing and utilized dietary xenobiotic taxon-specific milk miRNA (xenomiRs) as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells using adenovirus-type 5-mediated miRNA gene transfer. RESULTS: Mammals share many milk miRNAs yet exhibit taxon-specific miRNA fingerprints. We traced bovine-specific miRNAs from formula nutrition in human preterm stool and 9 d after the onset of enteral feeding in intestinal cells (ICs) of preterm piglets. Thereafter, several xenomiRs accumulated in the ICs. Moreover, a few hours after introducing enteral feeding in preterm piglets with supplemented reporter miRNAs (cel-miR-39-5p/-3p), we observed their enrichment in blood serum and in argonaute RISC catalytic component 2 (AGO2)-immunocomplexes from intestinal biopsies. CONCLUSIONS: Milk-derived miRNAs survived GI passage in human and porcine neonates. Bovine-specific miRNAs accumulated in ICs of preterm piglets after enteral feeding with bovine colostrum/formula. In piglets, colostrum supplementation with cel-miR-39-5p/-3p resulted in increased blood concentrations of cel-miR-39-3p and argonaute RISC catalytic component 2 (AGO2) loading in ICs. This suggests the possibility of vertical transmission of miRNA signaling from milk through the neonatal digestive tract.

The Overlooked Microbiome-Considering Archaea and Eukaryotes Using Multiplex Nanopore-16S-/18S-rDNA-Sequencing: A Technical Report Focusing on Nasopharyngeal Microbiomes.

In contrast to bacteria, microbiome analyses often neglect archaea, but also eukaryotes. This is partly because they are difficult to culture due to their demanding growth requirements, or some even have to be classified as uncultured microorganisms. Consequently, little is known about the relevance of archaea in human health and diseases. Contemporary broad availability and spread of next generation sequencing techniques now enable a stronger focus on such microorganisms, whose cultivation is difficult. However, due to the enormous evolutionary distances between bacteria, archaea and eukaryotes, the implementation of sequencing strategies for smaller laboratory scales needs to be refined to achieve as a holistic view on the microbiome as possible. Here, we present a technical approach that enables simultaneous analyses of archaeal, bacterial and eukaryotic microbial communities to study their roles in development and courses of respiratory disorders. We thus applied combinatorial 16S-/18S-rDNA sequencing strategies for sequencing-library preparation. Considering the lower total microbiota density of airway surfaces, when compared with gut microbiota, we optimized the DNA purification workflow from nasopharyngeal swab specimens. As a result, we provide a protocol that allows the efficient combination of bacterial, archaeal, and eukaryotic libraries for nanopore-sequencing using Oxford Nanopore Technologies MinION devices and subsequent phylogenetic analyses. In a pilot study, this workflow allowed the identification of some environmental archaea, which were not correlated with airway microbial communities before. Moreover, we assessed the protocol's broader applicability using a set of human stool samples. We conclude that the proposed protocol provides a versatile and adaptable tool for combinatorial studies on bacterial, archaeal, and eukaryotic microbiomes on a small laboratory scale.

The Adenovirus Vector Platform: Novel Insights into Rational Vector Design and Lessons Learned from the COVID-19 Vaccine.

The adenovirus vector platform remains one of the most efficient toolboxes for generation of transfer vehicles used in gene therapy and virotherapy to treat tumors, as well as vaccines to protect from infectious diseases. The adenovirus genome and capsids can be modified using highly efficient techniques, and vectors can be produced at high titers, which facilitates their rapid adaptation to current needs and disease applications. Over recent years, the adenovirus vector platform has been in the center of attention for vaccine development against the ongoing coronavirus SARS-CoV-2/COVID-19 pandemic. The worldwide deployment of these vaccines has greatly deepened the knowledge on virus-host interactions and highlighted the need to further improve the effectiveness and safety not only of adenovirus-based vaccines but also of gene therapy and oncolytic virotherapy vectors. Based on the current evidence, we discuss here how adenoviral vectors can be further improved by intelligent molecular design. This review covers the full spectrum of state-of-the-art strategies to avoid vector-induced side effects ranging from the vectorization of non-canonical adenovirus types to novel genome engineering techniques.

The Role of Insulin Receptor Substrate Proteins in Bronchopulmonary Dysplasia and Asthma: New Potential Perspectives.

Insulin receptor substrates (IRSs) are proteins that are involved in signaling through the insulin receptor (IR) and insulin-like growth factor (IGFR). They can also interact with other receptors including growth factor receptors. Thus, they represent a critical node for the transduction and regulation of multiple signaling pathways in response to extracellular stimuli. In addition, IRSs play a central role in processes such as inflammation, growth, metabolism, and proliferation. Previous studies have highlighted the role of IRS proteins in lung diseases, in particular asthma. Further, the members of the IRS family are the common proteins of the insulin growth factor signaling cascade involved in lung development and disrupted in bronchopulmonary dysplasia (BPD). However, there is no study focusing on the relationship between IRS proteins and BPD yet. Unfortunately, there is still a significant gap in knowledge in this field. Thus, in this review, we aimed to summarize the current knowledge with the major goal of exploring the possible roles of IRS in BPD and asthma to foster new perspectives for further investigations.

Microarray-Based Analyses of Rhinovirus Species-Specific Antibody Responses in Exacerbated Pediatric Asthma in a German Pediatric Cohort.

Rhinoviruses (RV) account for a significant number of asthma exacerbations, and RV species C may be associated with a severe course in vulnerable patient groups. Despite important evidence on the role of RV reported by clinicians and life scientists, there are still unanswered questions regarding their influence on asthma exacerbation in young patients. Thus, we measured the RVspecies-specific IgG titers in our German pediatric exacerbation cohort using a microarray-based technology. For this approach, human sera of patients with exacerbated asthma and wheeze, as well as healthy control subjects (n = 136) were included, and correlation analyses were performed. Concordantly with previously published results, we observed significantly higher cumulative levels of RV species A-specific IgG (p = 0.011) and RV-C-specific IgG (p = 0.051) in exacerbated asthma group compared to age-matched controls. Moreover, atopic wheezers had increased RV-specific IgG levels for species A (p = 0.0011) and species C (p = 0.0009) compared to non-atopic wheezers. Hypothesizing that bacterial infection positively correlates with immune memory against RV, we included nasopharyngeal swab results in our analyses and detected limited correlations. Interestingly, the eosinophil blood titer positively correlated with RV-specific IgG levels. With these observations, we add important observations to the existing data regarding exacerbation in pediatric and adolescent medicine. We propose that scientists and clinicians should pay more attention to the relevance of RV species in susceptible pediatric patients.

An Adenoviral Vector as a Versatile Tool for Delivery and Expression of miRNAs.

Only two decades after discovering miRNAs, our understanding of the functional effects of deregulated miRNAs in the development of diseases, particularly cancer, has been rapidly evolving. These observations and functional studies provide the basis for developing miRNA-based diagnostic markers or new therapeutic strategies. Adenoviral (Ad) vectors belong to the most frequently used vector types in gene therapy and are suitable for strong short-term transgene expression in a variety of cells. Here, we report the set-up and functionality of an Ad-based miRNA vector platform that can be employed to deliver and express a high level of miRNAs efficiently. This vector platform allows fast and efficient vector production to high titers and the expression of pri-miRNA precursors under the control of a polymerase II promoter. In contrast to non-viral miRNA delivery systems, this Ad-based miRNA vector platform allows accurate dosing of the delivered miRNAs. Using a two-vector model, we showed that Ad-driven miRNA expression was sufficient in down-regulating the expression of an overexpressed and highly stable protein. Additional data corroborated the downregulation of multiple endogenous target RNAs using the system presented here. Additionally, we report some unanticipated synergistic effects on the transduction efficiencies in vitro when cells were consecutively transduced with two different Ad-vectors. This effect might be taken into consideration for protocols using two or more different Ad vectors simultaneously.

Properties of Adenovirus Vectors with Increased Affinity to DSG2 and the Potential Benefits of Oncolytic Approaches and Gene Therapy.

Carcinomas are characterized by a widespread upregulation of intercellular junctions that create a barrier to immune response and drug therapy. Desmoglein 2 (DSG2) represents such a junction protein and serves as one adenovirus receptor. Importantly, the interaction between human adenovirus type 3 (Ad3) and DSG2 leads to the shedding of the binding domain followed by a decrease in the junction protein expression and transient tight junction opening. Junction opener 4 (JO-4), a small recombinant protein derived from the Ad3 fiber knob, was previously developed with a higher affinity to DSG2. JO-4 protein has been proven to enhance the effects of antibody therapy and chemotherapy and is now considered for clinical trials. However, the effect of the JO4 mutation in the context of a virus remains insufficiently studied. Therefore, we introduced the JO4 mutation to various adenoviral vectors to explore their infection properties. In the current experimental settings and investigated cell lines, the JO4-containing vectors showed no enhanced transduction compared with their parental vectors in DSG2-high cell lines. Moreover, in DSG2-low cell lines, the JO4 vectors presented a rather weakened effect. Interestingly, DSG2-negative cell line MIA PaCa-2 even showed resistance to JO4 vector infection, possibly due to the negative effect of JO4 mutation on the usage of another Ad3 receptor: CD46. Together, our observations suggest that the JO4 vectors may have an advantage to prevent CD46-mediated sequestration, thereby achieving DSG2-specific transduction.

Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis.

BACKGROUND: Recently, we provided evidence that a single nucleotide polymorphism (SNP), rs41266431, on the gap junction protein alpha 4 (GJA4) gene, acts as a modifier for clinical disease severity in patients with cystic fibrosis (CF). These features are very similar to those of variants of the mannose-binding lectin (MBL). This study aimed to clarify whether the clinical disease phenotype associated with GJA4 variants is independent of MBL variants. METHODS: One hundred and twelve patients with homozygous F508del (mean age, 27.6 years; m/f, 61/51) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. A sequence analysis was performed for GJA4 and MBL. The clinical phenotype was assessed over three years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, and inflammatory markers. RESULTS: A clinically relevant SNP of GJA4 was identified by sequence analysis. Pulmonary function (FVC% pred, mean 78/85; p < 0.055) and survival to end-stage lung disease were lower (p < 0.043) for this variant (rs41266431) in carriers homozygous for the G variant (n = 82/112; 73%) than in other carriers. Serum MBL (820/372 ng/mL, p < 0.001) was significantly higher in "MBL-sufficient" genotypes (n = 79/112; 71%) than in "MBL-insufficient" genotypes, and a trend for a significant difference in BMI percentiles (35.2/23.8; p < 0.059) was observed. For the MBL-sufficient genotype (median age at death, 38/26 years), there was a trend for better survival (p < 0.076). There was no augmentation by gene-gene interaction between MBL and GJA4 variants for any outcome parameter. CONCLUSIONS: The clinical disease phenotype associated with GJA4 variants is independent of MBL variants. MBL-sufficient variants were associated with superior BMI and a trend for better survival than MBL insufficient variants.

The Relevance of the Bacterial Microbiome, Archaeome and Mycobiome in Pediatric Asthma and Respiratory Disorders.

Bacteria, as well as eukaryotes, principally fungi, of the upper respiratory tract play key roles in the etiopathogenesis of respiratory diseases, whereas the potential role of archaea remains poorly understood. In this review, we discuss the contribution of all three domains of cellular life to human naso- and oropharyngeal microbiomes, i.e., bacterial microbiota, eukaryotes (mostly fungi), as well as the archaeome and their relation to respiratory and atopic disorders in infancy and adolescence. With this review, we aim to summarize state-of-the-art contributions to the field published in the last decade. In particular, we intend to build bridges between basic and clinical science.

Viral Infection and Respiratory Exacerbation in Children: Results from a Local German Pediatric Exacerbation Cohort.

Respiratory viruses play an important role in asthma exacerbation, and early exposure can be involved in recurrent bronchitis and the development of asthma. The exact mechanism is not fully clarified, and pathogen-to-host interaction studies are warranted to identify biomarkers of exacerbation in the early phase. Only a limited number of international exacerbation cohorts were studied. Here, we have established a local pediatric exacerbation study in Germany consisting of children with asthma or chronic, recurrent bronchitis and analyzed the viriome within the nasopharyngeal swab specimens derived from the entire cohort (n = 141). Interestingly, 41% of exacerbated children had a positive test result for human rhinovirus (HRV)/human enterovirus (HEV), and 14% were positive for respiratory syncytial virus (RSV). HRV was particularly prevalent in asthmatics (56%), wheezers (50%), and atopic (66%) patients. Lymphocytes were decreased in asthmatics and in HRV-infected subjects, and patients allergic to house dust mites were more susceptible to HRV infection. Our study thus confirms HRV infection as a strong 'biomarker' of exacerbated asthma. Further longitudinal studies will show the clinical progress of those children with a history of an RSV or HRV infection. Vaccination strategies and novel treatment guidelines against HRV are urgently needed to protect those high-risk children from a serious course of disease.

Increased Antibiotic Resistance in Children with Helicobacter pylori Infection: A Retrospective Study.

Children with recurrent abdominal pain may be suffering from a Helicobacterpylori (HP) infection. The gold standard for confirming HP gastritis is histological evaluation and microbiological tests performed on specimens collected by esophagogastroduodenoscopy (EGD). The aim of this study was to analyze HP positive cultures and antibiograms with regard to clinical and histopathological correlates. The data of 124 subjects with frequent gastrointestinal symptoms who underwent an EGD were retrospectively collected and analyzed. The mean age of the patients was 13 ± 3.6 years. The most frequent complaints were epigastric pain (84%; n = 100/119) and dyspepsia (79%; n = 94/119). HP gastritis was diagnosed in 54% (n = 67). Interestingly, 40% (n = 49) of the isolates were resistant to at least one antibiotic: amoxicillin (20%; n = 10/49), clarithromycin (45%; n = 22/49), or metronidazole (59%; n = 29/49). Isolates were resistant to two or more antibiotics in 16% (n = 20) of cases. In conclusion, we revealed remarkably high resistance rates to amoxicillin, metronidazole, and clarithromycin in our cohort. The presence of antibiotic resistance to more than one antibiotic was substantially increased in our HP-infected patients and this may negatively affect eradication treatment.

The Translational Role of MUC8 in Salivary Glands: A Potential Biomarker for Salivary Stone Disease?

Mucin (MUC) 8 has been shown to play an important role in respiratory disease and inflammatory responses. In the present study, we investigated the question of whether MUC8 is also produced and secreted by salivary glands and whether it may also play a role in the oral cavity in the context of inflammatory processes or in the context of salivary stone formation. Tissue samples from parotid and submandibular glands of body donors (n = 6, age range 63-88 years), as well as surgically removed salivary stones from patients (n = 38, age range 48-72 years) with parotid and submandibular stone disease were immunohistochemically analyzed targeting MUC8 and TNFα. The presence of MUC8 in salivary stones was additionally analyzed by dot blot analyses. Moreover, saliva samples from patients (n = 10, age range 51-72 years), who had a salivary stone of the submandibular gland on one side were compared with saliva samples from the other "healthy" side, which did not have a salivary stone, by ELISA. Positive MUC8 was detectable in the inter- and intralobular excretory ducts of both glands (parotid and submandibular). The glandular acini showed no reactivity. TNFα revealed comparable reactivity to MUC8 in the glandular excretory ducts and also did not react in glandular acini. Salivary stones demonstrated a characteristic distribution pattern of MUC8 that differed between parotid and submandibular salivary stones. The mean MUC8 concentration was 71.06 ng/mL in female and 33.21 ng/mL in male subjects (p = 0.156). Saliva from the side with salivary calculi contained significantly (15-fold) higher MUC8 concentration levels than saliva from the healthy side (p = 0.0005). MUC8 concentration in salivary stones varied from 4.59 ng/mL to 202.83 ng/mL. In females, the MUC8 concentration in salivary stones was significantly (2.3-fold) higher, with an average of 82.84 ng/mL compared to 25.27 ng/mL in male patients (p = 0.034). MUC8 is secreted in the excretory duct system of salivary glands and released into saliva. Importantly, MUC8 salivary concentrations vary greatly between individuals. In addition, the MUC8 concentration is gender-dependent (♀ > ♂). In the context of salivary stone diseases, MUC8 is highly secreted in saliva. The findings support a role for MUC8 in the context of inflammatory events and salivary stone formation. The findings allow conclusions on a gender-dependent component of MUC8.

The Communication between Ocular Surface and Nasal Epithelia in 3D Cell Culture Technology for Translational Research: A Narrative Review.

There is a lack of knowledge regarding the connection between the ocular and nasal epithelia. This narrative review focuses on conjunctival, corneal, ultrastructural corneal stroma, and nasal epithelia as well as an introduction into their interconnections. We describe in detail the morphology and physiology of the ocular surface, the nasolacrimal ducts, and the nasal cavity. This knowledge provides a basis for functional studies and the development of relevant cell culture models that can be used to investigate the pathogenesis of diseases related to these complex structures. Moreover, we also provide a state-of-the-art overview regarding the development of 3D culture models, which allow for addressing research questions in models resembling the in vivo situation. In particular, we give an overview of the current developments of corneal 3D and organoid models, as well as 3D cell culture models of epithelia with goblet cells (conjunctiva and nasal cavity). The benefits and shortcomings of these cell culture models are discussed. As examples for pathogens related to ocular and nasal epithelia, we discuss infections caused by adenovirus and measles virus. In addition to pathogens, also external triggers such as allergens can cause rhinoconjunctivitis. These diseases exemplify the interconnections between the ocular surface and nasal epithelia in a molecular and clinical context. With a final translational section on optical coherence tomography (OCT), we provide an overview about the applicability of this technique in basic research and clinical ophthalmology. The techniques presented herein will be instrumental in further elucidating the functional interrelations and crosstalk between ocular and nasal epithelia.

The Risk of Nonsteroidal Anti-Inflammatory Drugs in Pediatric Medicine: Listen Carefully to Children with Pain.

Over the last decades, the use of over-the-counter analgesics in the general population has increased in Germany. Ibuprofen is one of the most commonly used nonsteroidal anti-inflammatory drug (NSAID) and is frequently prescribed to children as an analgesic and/or antipyretic. Besides having a well-established safety and efficacy profile when used in appropriate doses, cases of NSAID-induced acute kidney injury (AKI) have been described in the pediatric population, particularly in the context of dehydration and in combination with other drugs. The ingestion of more than 400 mg/kg is associated with severe or life-threatening toxicity. This report is about two previously healthy adolescents, who developed AKI after taking high daily dose of ibuprofen as a pain reliever without any appropriate medical supervision. With these case reports, in addition to the side effect profiles of this analgesic, we would also like to present a certain therapeutic recommendation that we applied in these patients, and furthermore appeal to pediatricians to strictly set the indications for ibuprofen intake.

Enhanced Antiviral Function of Magnesium Chloride-Modified Heparin on a Broad Spectrum of Viruses.

Previous studies reported on the broad-spectrum antiviral function of heparin. Here we investigated the antiviral function of magnesium-modified heparin and found that modified heparin displayed a significantly enhanced antiviral function against human adenovirus (HAdV) in immortalized and primary cells. Nuclear magnetic resonance analyses revealed a conformational change of heparin when complexed with magnesium. To broadly explore this discovery, we tested the antiviral function of modified heparin against herpes simplex virus type 1 (HSV-1) and found that the replication of HSV-1 was even further decreased compared to aciclovir. Moreover, we investigated the antiviral effect against the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and measured a 55-fold decreased viral load in the supernatant of infected cells associated with a 38-fold decrease in virus growth. The advantage of our modified heparin is an increased antiviral effect compared to regular heparin.