Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Candida gut colonization, yeast species distribution, and biofilm production in Clostridioides difficile infected patients. A comparison between three populations in two different time periods

Candida gut colonization and yeast biofilm production capacity were investigated, by means of XTT reduction assay, in Clostridioides difficile infected (CDI) patients, in non-CDI diarrheic patients, and in healthy donors in two different time periods (2013–2015 and 2018–2019 respectively). Candida gut colonization was significantly (p &lt; 0.001) associated to C. difficile infection, and to patients infected with hypervirulent C. difficile strains bearing the tcdC deletion at nucleotide 117 (p = 0.0003). Although there was not a prevalent yeast species in CDI patients, C. albicans was the species significantly (p &lt; 0.001) associated to both the infections sustained by the non-hypervirulent C. difficile strains and those caused by the hypervirulent strain (p = 0.001). The biofilm production by the yeasts isolated from the CDI patients and from non-CDI diarrheic patients did not differ significantly. However, a significantly (p = 0.007) higher biofilm production was observed in the Candida strains, particularly C. albicans, isolated from healthy donors compared to that of the yeasts cultured from CDI patients. Seasonal occurrence was observed in the isolation rate of CDI and non-CDI diarrheic cases (p = 0.0019), peaking in winter for CDI patients and in spring for non-CDI diarrheic patients. Furthermore, seasonality emerged in the gut colonization by Candida of CDI patients in the winter. It seems, therefore, that the reduced capacity of biofilm production by Candida strains isolated from CDI patients might have a role in the development of C. difficile infection, probably facilitating the spread of the bacteria into the gut thus amplifying their pathogenic action

The Antimicrobial Peptide Esc(1-21) Synergizes with Colistin in Inhibiting the Growth and in Killing Multidrug Resistant <i>Acinetobacter baumannii</i> Strains

Multidrug-resistant microbial infections and the scarce availability of new antibiotics capable of eradicating them are posing a serious problem to global health security. Among the microorganisms that easily acquire resistance to antibiotics and that are the etiological cause of severe infections, there is Acinetobacter baumannii. Carbapenems are the principal agents used to treat A. baumannii infections. However, when strains develop resistance to this class of antibiotics, colistin is considered one of the last-resort drugs. However, the appearance of resistance to colistin also makes treatment of the Acinetobacter infections very difficult. Antimicrobial peptides (AMP) from the innate immunity hold promise as new alternative antibiotics due to their multiple biological properties. In this study, we characterized the activity and the membrane-perturbing mechanism of bactericidal action of a derivative of a frog-skin AMP, namely Esc(1-21), when used alone or in combination with colistin against multidrug-resistant A. baumannii clinical isolates. We found that the mixture of the two compounds had a synergistic effect in inhibiting the growth and killing of all of the tested strains. When combined at dosages below the minimal inhibitory concentration, the two drugs were also able to slow down the microbial growth and to potentiate the membrane-perturbing effect. To the best of our knowledge, this is the first report showing a synergistic effect between AMPs, i.e., Esc(1-21), and colistin against colistin-resistant A. baumannii clinical isolates, highlighting the potential clinical application of such combinational therapy

Novel splice-switching oligonucleotide promotes BRCA1 aberrant splicing and susceptibility to PARP inhibitor action

Tumors carrying hereditary mutations in BRCA1, which attenuate the BRCA1 DNA damage repair pathway, are more susceptible to dual treatment with PARP inhibitors and DNA damaging therapeutics. Conversely, breast cancer tumors with nonmutated functional BRCA1 are less sensitive to PARP inhibition. We describe a method that triggers susceptibility to PARP inhibition in BRCA1‐functional tumor cells. BRCA1 exon 11 is a key for the function of BRCA1 in DNA damage repair. Analysis of the BRCA1 exon 11 splicing mechanism identified a key region within this exon which, when deleted, induced exon 11 skipping. An RNA splice‐switching oligonucleotide (SSO) developed to target this region was shown to artificially stimulate skipping of exon 11 in endogenous BRCA1 pre‐mRNA. SSO transfection rendered wild‐type BRCA1 expressing cell lines more susceptible to PARP inhibitor treatment, as demonstrated by a reduction in cell survival at all SSO concentrations tested. Combined SSO and PARP inhibitor treatment increased γH2AX expression indicating that SSO‐dependent skipping of BRCA1 exon 11 was able to promote DSBs and therefore synthetic lethality. In conclusion, this SSO provides a new potential therapeutic strategy for targeting BRCA1‐functional breast cancer by enhancing the effect of PARP inhibitors

Single-centre retrospective analysis of the best timing for the QTc interval length assessment in neonates

Objective To evaluate the best timing for ECG screening in order to diagnose long QT syndrome and lower, at the same time, the false positives.Design We retrospectively evaluated the corrected QT (QTc) interval in the clinical reports of the ECG screening performed, as per internal protocol.Setting An outpatient setting in our Unit of Neonatology and Pediatrics, Santa Maria Goretti Hospital in Latina, Italy.Patients We enrolled 3467 healthy neonates between 14 and 30 days of life.Interventions The newborns with abnormal QTc interval were invited to subsequent revaluation every 21 days, until normalisation or necessity to refer to a tertiary paediatric cardiology centre.Main outcome measures Difference in QTc according to patients’ characteristics and number of false positives at second ECG evaluation.Results At first evaluation, 249 (7.2%) newborns had prolonged QTc. We did not find any significant difference in the QTc length according to gestational age (p=0.40) and birth weight (p=0.81). As expected, girls had longer QTc than boys (p=0.01). Only 11 out of 240 (4.6%) and 1 out of 238 infants (0.4%) had persistently prolonged QTc at second and third ECG evaluation, respectively. The QTc decreased significantly at second (p&lt;0.0001) and third evaluation (p=0.0035).Conclusions In our study, we showed that a single screening performed in healthy infants after 60 days of life could reduce the risk of false positives, with a beneficial impact on public national health system and the chance to start early therapy in case of long QT syndrome

Dawe, Reginald

CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external genitalia. In a cohort of Brazilian patients, we identified mutations in HSD17B3 and SRD5A2 which are both required for human sexual differentiation. A number of these mutations occurred within regions potentially critical for splicing regulation. Minigenes were used to validate the functional effect of mutations in both genes. We evaluated the c. 277 + 2 T gt; G mutation in HSD17B3, and the c. 544 G gt; A, c. 548-44 T gt; G and c. 278delG mutations in SRD5A2. We demonstrated that these mutations altered the splicing pattern of these genes. In a genomic era these results illustrate, and remind us, that sequence variants within exon-intron boundaries, which are primarily identified for diagnostic purposes and have unknown pathogenicity, need to be assessed with regards to their impact not only on protein expression, but also on mRNA splicing71CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOPDSE-0211/13-3sem informação2011/24119-

A study of splicing mutations in disorders of sex development

The presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external genitalia. In a cohort of Brazilian patients, we identified mutations in HSD17B3 and SRD5A2 which are both required for human sexual differentiation. A number of these mutations occurred within regions potentially critical for splicing regulation. Minigenes were used to validate the functional effect of mutations in both genes. We evaluated the c.277 + 2 T &gt; G mutation in HSD17B3, and the c.544 G &gt; A, c.548-44 T &gt; G and c.278delG mutations in SRD5A2. We demonstrated that these mutations altered the splicing pattern of these genes. In a genomic era these results illustrate, and remind us, that sequence variants within exon-intron boundaries, which are primarily identified for diagnostic purposes and have unknown pathogenicity, need to be assessed with regards to their impact not only on protein expression, but also on mRNA splicing

Exposure to b-LED Light While Exerting Antimicrobial Activity on Gram-Negative and -Positive Bacteria Promotes Transient EMT-like Changes and Growth Arrest in Keratinocytes

While blue LED (b-LED) light is increasingly being studied for its cytotoxic activity towards bacteria in therapy of skin-related infections, its effects on eukaryotic cells plasticity are less well characterized. Moreover, since different protocols are often used, comparing the effect of b-LED towards both microorganisms and epithelial surfaces may be difficult. The aim of this study was to analyze, in the same experimental setting, both the bactericidal activity and the effects on human keratinocytes. Exposure to b-LED induced an intense cytocidal activity against Gram-positive (i.e, Staphylococcus aureus) and Gram-negative (i.e., Pseudomonas aeruginosa) bacteria associated with catheter-related infections. Treatment with b-LED of a human keratinocyte cell line induced a transient cell cycle arrest. At the molecular level, exposure to b-LED induced a transient downregulation of Cyclin D1 and an upregulation of p21, but not signs of apoptosis. Interestingly, a transient induction of phosphor-histone γ-H2Ax, which is associated with genotoxic damages, was observed. At the same time, keratinocytes underwent a transient epithelial to mesenchymal transition (EMT)-like phenotype, characterized by E-cadherin downregulation and SNAIL/SLUG induction. As a functional readout of EMT induction, a scratch assay was performed. Surprisingly, b-LED treatment provoked a delay in the scratch closure. In conclusion, we demonstrated that b-LED microbicidal activity is associated with complex responses in keratinocytes that certainly deserve further analysis

Three-year COVID-19 and flu vaccinations among medical residents in a tertiary hospital in Italy: The threat of acceptance decline in seasonal campaigns

: The COVID-19 vaccination campaign in Italy started in December 2020, and, due to the Omicron variant's emergence, a second booster dose was recommended for high-risk individuals and healthcare workers from July 2022. The aim of the study was to evaluate the vaccination coverages for the COVID-19 second booster dose and to identify predictors of its acceptance within the population of medical residents (MRs) of the Fondazione Policlinico Universitario "A. Gemelli" IRCCS (FPG) University Hospital. The study was conducted at FPG from October 4th to December 21st, 2022, and COVID-19 second booster dose and influenza vaccines were administered. The study analyzed collected data and conducted multivariate logistic regressions to explore potential predictors of vaccination adherence. The analyses performed were compared with the sample enrolled in FPG residency programs at the start of the COVID-19 vaccination campaign. 1968 MRs were involved in the 2022-2023 vaccination campaign (mean age 28.97, SD 3.44), and the second booster dose of COVID-19 vaccination coverage was low (18.80%). Almost all participants opted for co-administration of COVID-19 and influenza vaccinations, leading to a similar rate of influenza vaccination coverage (16.26%). Being a frontline resident, meaning a direct involvement in managing COVID-19 patients and vaccination campaigns, was the main predictor of vaccination adherence (OR 1.72, 95% CI 1.25-2.17). The dropping in influenza vaccination coverage in 2022-2023 and the low adherence to COVID-19 second booster dose among young physicians is concerning, calling for tailored vaccination campaigns and interventions

Immunocompromised patients with acute respiratory distress syndrome : Secondary analysis of the LUNG SAFE database

The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013