An epidemiological investigation of high-risk infants for Respiratory Syncytial Virus infections: a retrospective cohort study.

BACKGROUND: Respiratory Syncytial Virus (RSV) infections may lead to severe consequences in infants born preterm with breathing problems (such as bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS)) or congenital heart diseases (CHD). Since studies investigating the influence of different gestational age (WGA) and concomitant specific comorbidities on the burden of RSV infections are scarce, the present study aimed to better characterize these high-risk populations in the Italian context. METHODS: This retrospective, longitudinal and record-linkage cohort study involved infants born between 2017 and 2019 in Lazio Region (Italy) and is based on data extracted from administrative databases. Each infant was exclusively included in one of the following cohorts: (1) BPD-RDS (WGA ≤35 with or without CHD) or (2) CHD (without BPD and/or RDS) or (3) Preterm (WGA ≤35 without BPD (and/or RDS) or CHD). Each cohort was followed for 12 months from birth. Information related to sociodemographic at birth, and RSV and Undetermined Respiratory Agents (URA) hospitalizations and drug consumption at follow-up were retrieved and described. RESULTS: A total of 8,196 infants were selected and classified as 1,084 BPD-RDS, 3,286 CHD and 3,826 Preterm. More than 30% of the BPD-RDS cohort was composed by early preterm infants (WGA ≤ 29) in contrast to the Preterm cohort predominantly constitute by moderate preterm infants (98.2%), while CHD infants were primarily born at term (83.9%). At follow-up, despite the cohorts showed similar proportions of RSV hospitalizations, in BPD-RDS cohort hospitalizations were more frequently severe compared to those occurred in the Preterm cohort (p<0.01), in the BPD-RDS cohort was also found the highest proportion of URA hospitalizations (p<0.0001). In addition, BPD-RDS infants, compared to those of the remaining cohorts, received more frequently prophylaxis with palivizumab (p<0.0001) and were more frequently treated with adrenergics inhalants, and glucocorticoids for systemic use. CONCLUSIONS: The assessment of the study clinical outcomes highlighted that, the demographic and clinical characteristics at birth of the study cohorts influence their level of vulnerability to RSV and URA infections. As such, continuous monitoring of these populations is necessary in order to ensure a timely organization of health care system able to respond to their needs in the future.

Identification of SOX2 Interacting Proteins in the Developing Mouse Lung With Potential Implications for Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia is a structural birth defect of the diaphragm, with lung hypoplasia and persistent pulmonary hypertension. Aside from vascular defects, the lungs show a disturbed balance of differentiated airway epithelial cells. The Sry related HMG box protein SOX2 is an important transcription factor for proper differentiation of the lung epithelium. The transcriptional activity of SOX2 depends on interaction with other proteins and the identification of SOX2-associating factors may reveal important complexes involved in the disturbed differentiation in CDH. To identify SOX2-associating proteins, we purified SOX2 complexes from embryonic mouse lungs at 18.5 days of gestation. Mass spectrometry analysis of SOX2-associated proteins identified several potential candidates, among which were the Chromodomain Helicase DNA binding protein 4 (CHD4), Cut-Like Homeobox1 (CUX1), and the Forkhead box proteins FOXP2 and FOXP4. We analyzed the expression patterns of FOXP2, FOXP4, CHD4, and CUX1 in lung during development and showed co-localization with SOX2. Co-immunoprecipitations validated the interactions of these four transcription factors with SOX2, and large-scale chromatin immunoprecipitation (ChIP) data indicated that SOX2 and CHD4 bound to unique sites in the genome, but also co-occupied identical regions, suggesting that these complexes could be involved in co-regulation of genes involved in the respiratory system.

A 'Multiomic' Approach of Saliva Metabolomics, Microbiota, and Serum Biomarkers to Assess the Need of Hospitalization in Coronavirus Disease 2019.

BACKGROUND AND AIMS: The SARS-CoV-2 pandemic has overwhelmed the treatment capacity of the health care systems during the highest viral diffusion rate. Patients reaching the emergency department had to be either hospitalized (inpatients) or discharged (outpatients). Still, the decision was taken based on the individual assessment of the actual clinical condition, without specific biomarkers to predict future improvement or deterioration, and discharged patients often returned to the hospital for aggravation of their condition. Here, we have developed a new combined approach of omics to identify factors that could distinguish coronavirus disease 19 (COVID-19) inpatients from outpatients. METHODS: Saliva and blood samples were collected over the course of two observational cohort studies. By using machine learning approaches, we compared salivary metabolome of 50 COVID-19 patients with that of 270 healthy individuals having previously been exposed or not to SARS-CoV-2. We then correlated the salivary metabolites that allowed separating COVID-19 inpatients from outpatients with serum biomarkers and salivary microbiota taxa differentially represented in the two groups of patients. RESULTS: We identified nine salivary metabolites that allowed assessing the need of hospitalization. When combined with serum biomarkers, just two salivary metabolites (myo-inositol and 2-pyrrolidineacetic acid) and one serum protein, chitinase 3-like-1 (CHI3L1), were sufficient to separate inpatients from outpatients completely and correlated with modulated microbiota taxa. In particular, we found Corynebacterium 1 to be overrepresented in inpatients, whereas Actinomycetaceae F0332, Candidatus Saccharimonas, and Haemophilus were all underrepresented in the hospitalized population. CONCLUSION: This is a proof of concept that a combined omic analysis can be used to stratify patients independently from COVID-19.

mRNA COVID-19 vaccine booster fosters B- and T-cell responses in immunocompromised patients.

SARS-CoV-2 vaccination has proven effective in inducing an immune response in healthy individuals and is progressively us allowing to overcome the pandemic. Recent evidence has shown that response to vaccination in some vulnerable patients may be diminished, and it has been proposed a booster dose. We tested the kinetic of development of serum antibodies to the SARS-CoV-2 Spike protein, their neutralizing capacity, the CD4 and CD8 IFN-γ T-cell response in 328 subjects, including 131 immunocompromised individuals (cancer, rheumatologic, and hemodialysis patients), 160 health-care workers (HCW) and 37 subjects older than 75 yr, after vaccination with two or three doses of mRNA vaccines. We stratified the patients according to the type of treatment. We found that immunocompromised patients, depending on the type of treatment, poorly respond to SARS-CoV-2 mRNA vaccines. However, an additional booster dose of vaccine induced a good immune response in almost all of the patients except those receiving anti-CD20 antibody. Similarly to HCW, previously infected and vaccinated immunocompromised individuals demonstrate a stronger SARS-CoV-2-specific immune response than those who are vaccinated without prior infection.

Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer.

Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non-muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosphorylation. This favored increased mitochondrial permeability leading to the cytoplasmic release of mitochondrial DNA, which activated the inflammasome for efficient IL-1ß (interleukin-1ß) secretion that promoted dendritic cell maturation. Resistance to ICD was associated with mitochondrial dysfunction related to low abundance of complex I of the respiratory chain. Analysis of complex I in patient tumors indicated that low abundance of this mitochondrial complex was associated with recurrence incidence after chemotherapy in patients with NMIBC. The identification of mitochondria-mediated ICD as a mechanism of action of MMC offers opportunities to optimize bladder cancer management and provides potential markers of treatment efficacy that could be used for patient stratification.

The Microbiome of Catheter Collected Urine in Males with Bladder Cancer According to Disease Stage.

PURPOSE: The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiome has been linked to many urological disorders. We tested the hypothesis that the urinary microbial composition may be different between men with or without bladder cancer in catheter collected urines, bladder washouts and midstream voided urines, and may be dependent on tumor staging. MATERIALS AND METHODS: Liquid samples were collected from male patients with bladder cancer, and sex and age matched nonneoplastic controls. Total DNA was extracted and processed for 16S rRNA gene sequencing. Bioinformatic analysis for microbial classification was performed to assess diversity and variations. RESULTS: The urinary microbiome associated with catheter collected urine samples of patients with bladder cancer was characterized by a significantly increased abundance of Veillonella (p=0.04) and Corynebacterium (p=0.03), and decreased Ruminococcus (p=0.03) compared to controls, with differences exacerbating with disease progression. Compared to catheterized urines, bladder cancer washouts showed the specific increase of some taxa, like Burkholderiaceae (p=0.014), whereas midstream urines were enriched in Streptococcus (p <0.0001), Enterococcus (p <0.0001), Corynebacterium (p=0.038) and Fusobacterium (p <0.0001). CONCLUSIONS: The bladder is colonized by endogenous bacteria and microbial modifications characterize the microbiome of patients with bladder cancer. Different microbial compositions can be characterized by changing sampling strategy. These results pave the way for exploring new diagnostic and therapeutic options based on the manipulation of the bacterial community.

Endogenous murine microbiota member Faecalibaculum rodentium and its human homologue protect from intestinal tumour growth.

The microbiota has been shown to promote intestinal tumourigenesis, but a possible anti-tumourigenic effect has also been postulated. Here, we demonstrate that changes in the microbiota and mucus composition are concomitant with tumourigenesis. We identified two anti-tumourigenic strains of the microbiota-Faecalibaculum rodentium and its human homologue, Holdemanella biformis-that are strongly under-represented during tumourigenesis. Reconstitution of ApcMin/+ or azoxymethane- and dextran sulfate sodium-treated mice with an isolate of F. rodentium (F. PB1) or its metabolic products reduced tumour growth. Both F. PB1 and H. biformis produced short-chain fatty acids that contributed to control protein acetylation and tumour cell proliferation by inhibiting calcineurin and NFATc3 activation in mouse and human settings. We have thus identified endogenous anti-tumourigenic bacterial strains with strong diagnostic, therapeutic and translational potential.