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

Dérégulation de l'expression des ADN polymérases translésionnelles, instabilité génétique et progression des cancers colorectaux et du sein

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

DNA polymerase theta up-regulation is associated with poor survival in breast cancer, perturbs DNA replication, and promotes genetic instability

“Replicative stress” is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase θ (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer

First-in-human first-in-class phase I trial of murlentamab, an anti-Mullerian-hormone receptor II (AMHRII) monoclonal antibody acting through tumor-associated macrophage (TAM) engagement, as single agent and in combination with carboplatin (C) and paclitaxel (P) in AMHRII-expressing advanced/metastatic gynecological cancer patients (pts)

International audience2521 Background: Membranous expression of AMHRII is found in ~70% of gynecological tumors. Murlentamab (M) binds with high affinity both AMHRII (at cell membrane) and CD16 (on macrophage, via its low fucose Fc). M reprograms TAMs, restoring their antitumoral functions (phagocytosis) resulting in cytotoxic T cell reactivation. Methods: Pts with advanced/metastatic AMHRII-expressing ovarian, cervical or endometrial cancer with measurable disease and performance status ≤ 1 received M as single agent (SA) in 8 dose escalating and 2 expansion cohorts. Combination with CP was studied in 2 escalating cohorts. Safety, recommended dose determination, antitumor activity, pharmacodynamics (PD) effects (circulating immune cells and tumor microenvironment (TME) from paired biopsies) were assessed. Results: 68 heavily pretreated (median 4 prior lines) pts received M for 0.5 to 11 months (mo) (59 pts M SA and 9 pts M + CP). No dose limiting toxicity was reported. Most common toxicity was G1-2 asthenia (29 %). Eight pts (12%) had G ≥ 3 reversible toxicities (asthenia, nausea/vomiting, anorexia, arthralgia). No antidrug antibody was detected. One partial response (PR) was achieved with M SA in a granulosa pt. In CP combination, 4/9 pts (44%) responded to treatment (1 Complete Response and 3 PRs). Overall, 22/67 (33%) pts were progression-free at 4 mos. Among 17 pts treated ≥ 6 mos, 6/9 (67%) granulosa pts with M SA and 4/5 (80%) endometrium and cervix with CP combination had a longer PFS than under previous regimen. PD blood assessment of 25 pts treated with M SA showed an increase in classical monocytes, and T cells and neutrophils activation. Changes in TME under M will be presented. Conclusions: Murlentamab was very well tolerated, demonstrated immune PD effects and showed hints of antitumor activity. These results together with its innovative immunological mode of action support development of M in AMHRII-expressing cancers, in combination with chemotherapy or other immune oncology drugs. Clinical trial information: NCT02978755

Persistent headaches one year after bacterial meningitis: prevalence, determinants and impact on quality of life

International audienceBackground: Little is known on headaches long-term persistence after bacterial meningitis and on their impact on patients' quality of life.Methods: In an ancillary study of the French national prospective cohort of community-acquired bacterial meningitis in adults (COMBAT) conducted between February 2013 and July 2015, we collected self-reported headaches before, at onset, and 12 months (M12) after meningitis. Determinants of persistent headache (PH) at M12, their association with M12 quality of life (SF 12), depression (Center for Epidemiologic Studies Depression Scale) and neuro-functional disability were analysed.Results: Among the 277 alive patients at M12 87/274 (31.8%), 213/271 (78.6%) and 86/277 (31.0%) reported headaches before, at the onset, and at M12, respectively. In multivariate analysis, female sex (OR: 2.75 [1.54-4.90]; p < 0.001), pre-existing headaches before meningitis (OR: 2.38 [1.32-4.30]; p < 0.01), higher neutrophilic polynuclei percentage in the CSF of the initial lumbar puncture (OR: 1.02 [1.00-1.04]; p < 0.05), and brain abscess during the initial hospitalisation (OR: 8.32 [1.97-35.16]; p < 0.01) were associated with M12 persistent headaches. Neither the responsible microorganism, nor the corticoids use were associated with M12 persistent headaches. M12 neuro-functional disability (altered Glasgow Outcome Scale; p < 0.01), M12 physical handicap (altered modified Rankin score; p < 0.001), M12 depressive symptoms (p < 0.0001), and M12 altered physical (p < 0.05) and mental (p < 0.0001) qualities of life were associated with M12 headaches.Conclusion: Persistent headaches are frequent one year after meningitis and are associated with quality of life alteration

One-Year Sequelae and Quality of Life in Adults with Meningococcal Meningitis: Lessons from the COMBAT Multicentre Prospective Study

Trial registration: ClinicalTrial.Gov identification number NCT01730690.International audienceIntroduction: COMBAT is a prospective, multicentre cohort study that enrolled consecutive adults with community-acquired bacterial meningitis (CABM) in 69 participating centres in France between February 2013 and July 2015 and followed them for 1 year.Methods: Patients aged at least 18 years old, hospitalised with CABM were followed during their hospitalisation and then contacted by phone 12 months after enrolment. Here we present the prevalence of sequelae at 12 months in a subgroup of patients with meningococcal meningitis.Results: Five of the 111 patients with meningococcal meningitis died during initial hospitalisation and two died between discharge and 12 months, leaving 104 patients alive 1 year after enrolment, 71 of whom provided 12-month follow-up data. The median age was 30.0 years and 54.1% of the patients had no identified risk factor for meningitis. More than 30% reported persistent headache, more than 40% were not satisfied with their sleep and 10% had concentration difficulties. Hearing loss was present in about 15% of the patients and more than 30% had depressive symptoms. About 13% of the patients with a previous professional activity had not resumed work. On the SF-12 Health Survey, almost 50% and 30% had physical component or mental component scores lower than the 25th percentile of the score distribution in the French general population. There was a non-significant improvement in the patients' disability scores from hospital discharge to 12 months (p = 0.16), but about 10% of the patients had residual disability.Conclusions: Although most patients in our cohort survive meningococcal meningitis, the long-term burden is substantial and therefore it is important to ensure a prolonged follow-up of survivors and to promote preventive strategies, including vaccination

Relationship between serotypes, disease characteristics and 30-day mortality in adults with invasive pneumococcal disease

International audienc

Impact on disease mortality of clinical, biological, and virological characteristics at hospital admission and overtime in COVID‐19 patients

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