Analysis of nucleic acid chaperoning by the prion protein and its inhibition by oligonucleotides

Prion diseases are unique neurodegenerative illnesses associated with the conversion of the cellular prion protein (PrPC) into the aggregated misfolded scrapie isoform, named PrPSc. Recent studies on the physiological role of PrPC revealed that this protein has probably multiple functions, notably in cell–cell adhesion and signal transduction, and in assisting nucleic acid folding. In fact, in vitro findings indicated that the human PrP (huPrP) possesses nucleic acid binding and annealing activities, similarly to nucleic acid chaperone proteins that play essential roles in cellular DNA and RNA metabolism. Here, we show that a peptide, representing the N-terminal domain of huPrP, facilitates nucleic acid annealing by two parallel pathways nucleated through the stem termini. We also show that PrP of human or ovine origin facilitates DNA strand exchange, ribozyme-directed cleavage of an RNA template and RNA trans-splicing in a manner similar to the nucleocapsid protein of HIV-1. In an attempt to characterize inhibitors of PrP-chaperoning in vitro we discovered that the thioaptamer 5′-GACACAAGCCGA-3′ was extensively inhibiting the PrP chaperoning activities. At the same time a recently characterized methylated oligoribonucleotide inhibiting the chaperoning activity of the HIV-1 nucleocapsid protein was poorly impairing the PrP chaperoning activities

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Burnout syndrome in critical care nursing staff.

International audienceRATIONALE: Burnout syndrome (BOS) associated with stress has been documented in health care professionals in many specialties. The intensive care unit (ICU) is a highly stressful environment. Little is known about BOS in critical care nursing staff. OBJECTIVES: To identify determinants of BOS in critical care nurses. METHODS: We conducted a questionnaire survey in France. Among 278 ICUs contacted for the study, 165 (59.4%) included 2,525 nursing staff members, of whom 2,392 returned questionnaires with complete Maslach Burnout Inventory data. MEASUREMENTS AND MAIN RESULTS: Of the 2,392 respondents (82% female), 80% were nurses, 15% nursing assistants, and 5% head nurses. Severe BOS-related symptoms were identified in 790 (33%) respondents. By multivariate analysis, four domains were associated with severe BOS: (1) personal characteristics, such as age (odds ratio [OR], 0.97/yr; confidence interval [CI], 0.96-0.99; p=0.0008); (2) organizational factors, such as ability to choose days off (OR, 0.69; CI, 0.52-0.91; p=0.009) or participation in an ICU research group (OR, 0.74; CI, 0.56-0.97; p=0.03); (3) quality of working relations (1-10 scale), such as conflicts with patients (OR, 1.96; CI, 1.16-1.30; p=0.01), relationship with head nurse (OR, 0.92/point; CI, 0.86-0.98; p=0.02) or physicians (OR, 0.81; CI, 0.74-0.87; p=0.0001); and (4) end-of-life related factors, such as caring for a dying patient (OR, 1.39; CI, 1.04-1.85; p=0.02), and number of decisions to forego life-sustaining treatments in the last week (OR, 1.14; CI, 1.01-1.29; p=0.04). CONCLUSION: One-third of ICU nursing staff had severe BOS. Areas for improvement identified in our study include conflict prevention, participation in ICU research groups, and better management of end-of-life care. Interventional studies are needed to investigate these potentially preventive strategies

Safety of performing fiberoptic bronchoscopy in critically ill hypoxemic patients with acute respiratory failure.: Bronchoscopy in Hypoxemic Patients

International audienceBACKGROUND: The safety of fiberoptic bronchoscopy (FOB) in nonintubated critically ill patients with acute respiratory failure has not been extensively evaluated. We aimed to measure the incidence of intubation and the need to increase ventilatory support following FOB and to identify predictive factors for this event. METHODS: A prospective multicenter observational study was carried out in eight French adult intensive care units. The study included 169 FOB performed in patients with a PaO(2)/FiO(2) ratio ≤ 300. The main end-point was intubation rate. The secondary end-point was rate of increased ventilatory support defined as an increase in oxygen requirement >50 %, the need to start noninvasive positive pressure ventilation (NI-PPV) or increase NI-PPV support. RESULTS: Within 24 h, an increase in ventilatory support was required following 59 bronchoscopies (35 %), of which 25 (15 %) led to endotracheal intubation. The existence of chronic obstructive pulmonary disease (COPD; OR 5.2, 95 % CI 1.6-17.8; p = 0.007) or immunosuppression (OR 5.4, 95 % CI 1.7-17.2; p = 0.004] were significantly associated with the need for intubation in the multivariable analysis. None of the baseline physiological parameters including the PaO(2)/FiO(2) ratio was associated with intubation. CONCLUSIONS: Bronchoscopy is often followed by an increase in ventilatory support in hypoxemic critically ill patients, but less frequently by the need for intubation. COPD and immunosuppression are associated with the need for invasive ventilation in the 24 h following bronchoscopy

Impact of species and antibiotic therapy of enterococcal peritonitis on 30-day mortality in critical care—an analysis of the OUTCOMEREA database

International audienceIntroduction: Enterococcus species are associated with an increased morbidity in intraabdominal infections (IAI). However, their impact on mortality remains uncertain. Moreover, the influence on outcome of the appropriate or inappropriate status of initial antimicrobial therapy (IAT) is subjected to debate, except in septic shock. The aim of our study was to evaluate whether an IAT that did not cover Enterococcus spp. was associated with 30-day mortality in ICU patients presenting with IAI growing with Enterococcus spp.Material and methods: Retrospective analysis of French database OutcomeRea from 1997 to 2016. We included all patients with IAI with a peritoneal sample growing with Enterococcus. Primary endpoint was 30-day mortality.Results: Of the 1017 patients with IAI, 76 (8%) patients were included. Thirty-day mortality in patients with inadequate IAT against Enterococcus was higher (7/18 (39%) vs 10/58 (17%), p = 0.05); however, the incidence of postoperative complications was similar. Presence of Enterococcus spp. other than E. faecalis alone was associated with a significantly higher mortality, even greater when IAT was inadequate. Main risk factors for having an Enterococcus other than E. faecalis alone were as follows: SAPS score on day 0, ICU-acquired IAI, and antimicrobial therapy within 3 months prior to IAI especially with third-generation cephalosporins. Univariate analysis found a higher hazard ratio of death with an Enterococcus other than E. faecalis alone that had an inadequate IAT (HR = 4.4 [1.3-15.3], p = 0.019) versus an adequate IAT (HR = 3.1 [1.0-10.0], p = 0.053). However, after adjusting for confounders (i.e., SAPS II and septic shock at IAI diagnosis, ICU-acquired peritonitis, and adequacy of IAT for other germs), the impact of the adequacy of IAT was no longer significant in multivariate analysis. Septic shock at diagnosis and ICU-acquired IAI were prognostic factors.Conclusion: An IAT which does not cover Enterococcus is associated with an increased 30-day mortality in ICU patients presenting with an IAI growing with Enterococcus, especially when it is not an E. faecalis alone. It seems reasonable to use an IAT active against Enterococcus in severe postoperative ICU-acquired IAI, especially when a third-generation cephalosporin has been used within 3 months

EPICANCER—Cancer Patients Presenting to the Emergency Departments in France: A Prospective Nationwide Study

Background: We aimed to estimate the prevalence of cancer patients who presented to Emergency Departments (EDs), report their chief complaint and identify the predictors of 30-day all-cause mortality. Patients and methods: we undertook a prospective, cross-sectional study during three consecutive days in 138 EDs and performed a logistic regression to identify the predictors of 30-day mortality in hospitalized patients. Results: A total of 1380 cancer patients were included. The prevalence of cancer patients among ED patients was 2.8%. The most frequent reasons patients sought ED care were fatigue (16.6%), dyspnea (16.3%), gastro-intestinal disorders (15.1%), trauma (13.0%), fever (12.5%) and neurological disorders (12.5%). Patients were admitted to the hospital in 64.9% of cases, of which 13.4% died at day 30. Variables independently associated with a higher mortality at day 30 were male gender (Odds Ratio (OR), 1.63; 95% CI, 1.04–2.56), fatigue (OR, 1.65; 95% CI, 1.01–2.67), poor performance status (OR, 3.00; 95% CI, 1.87–4.80), solid malignancy (OR, 3.05; 95% CI, 1.26–7.40), uncontrolled malignancy (OR, 2.27; 95% CI, 1.36–3.80), ED attendance for a neurological disorder (OR, 2.38; 95% CI, 1.36–4.19), high shock-index (OR, 1.80; 95% CI, 1.03–3.13) and oxygen therapy (OR, 2.68; 95% CI, 1.68–4.29). Conclusion: Cancer patients showed heterogeneity among their reasons for ED attendance and a high need for hospitalization and case fatality. Malignancy and general health status played a major role in the patient outcomes. This study suggests that the emergency care of cancer patients may be complex. Thus, studies to assess the impact of a dedicated oncology curriculum for ED physicians are warranted

Treatment intensity and outcome of nonagenarians selected for admission in ICUs: a multicenter study of the Outcomerea Research Group

International audienceBACKGROUND: Outcome of very elderly patients admitted in intensive care unit (ICU) was most often reported for octogenarians. ICU admission demands for nonagenarians are increasing. The primary objective was to compare outcome and intensity of treatment of octogenarians and nonagenarians. METHODS: We performed an observational study in 12 ICUs of the Outcomerea network which prospectively upload data into the Outcomerea database. Patients \textgreater90 years old (case patients) were matched with patients 80-90 years old (control patients). Matching criteria were severity of illness at admission, center, and year of admission. RESULTS: A total of 2419 patients aged 80 or older and admitted from September 1997 to September 2013 were included. Among them, 179 (7.9 %) were \textgreater90 years old. Matching was performed for 176 nonagenarian patients. Compared with control patients, case patients were more often hospitalized for unscheduled surgery [54 (30.7 %) vs. 42 (23.9 %), p \textless 0.01] and had less often arterial monitoring for blood pressure [37 (21 %) vs. 53 (30.1 %), p = 0.04] and renal replacement therapy [5 (2.8 %) vs. 14 (8 %), p = 0.05] than control patients. ICU [44 (25 %) vs. 36 (20.5 %), p = 0.28] or hospital mortality [70 (39.8 %) vs. 64 (36.4 %), p = 0.46] and limitation of life-sustaining therapies were not significantly different in case versus control patients, respectively. Only 16/176 (14 %) of case patients were transferred to a geriatric unit. CONCLUSION: This multicenter study reported that nonagenarians represented a small fraction of ICU patients. When admitted, these highly selected patients received similar life-sustaining treatments, except RRT, than octogenarians. ICU and hospital mortality were similar between the two groups

Systemic autoimmune disorders associated with thrombotic microangiopathy: A cross-sectional analysis from the French National TMA registry: Systemic autoimmune disease-associated TMA

International audienceContext - The management of systemic auto-immune diseases (SAID) -associated thrombotic microangiopathies (TMA) [SAID-TMA] remains debated. Objectives - To provide a demographic, clinical and therapeutic picture of SAID-TMA. Methods - A cross-sectional analysis was conducted on adult patients presenting with SAID and TMA from the French National TMA Registry over a 20-year period. Clinical features were extracted and compared to those from a historical cohort of atypical haemolytic and uremic syndrome (aHUS) patients. Results - Forty-one patients with SAID-TMA were compared to 78 patients with aHUS from a historical cohort. Connective tissue diseases (CTD) were systemic lupus erythematosus (n=18), primary Sjögren's syndrome (n=7), systemic sclerosis (n=11), mixed CTD (n=2) and 2 cases of vasculitides, including 7 overlapping forms and 8 cases of primary antiphospholipid syndromes (APLS). Patients with SAID-TMA generally had pre-existing chronic kidney failure (OR= 3.17, 95%CI: 1.204 to 7.923; p= 0.016) compared to aHUS patients, though creatinine levels were significantly lower (216 [IQR, 108-334] µmol/L vs. 368 [IQR, 170-722] µmol/L; p= 0.002). Patients were less likely to recover if renal replacement therapy was needed at onset (OR= 0.07; 0.02 to 0.34; p 0.05). Conclusion - The management of SAID-TMA implies an early initiation of immunosuppressive drugs for flares of the associated SAID, whereas TPE seem ineffective. KEY MESSAGES