Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Intrusions in story recall: When over-learned information interferes with episodic memory recall. Evidence from Alzheimer\u2019s disease.

Patients with Alzheimer\u2019s disease (AD) suffer from distortions of memory. Among such distortions, intrusions in memory tests are frequently observed. In this study we describe the performance of a group of mild AD patients and a group of normal controls on the recall of three different types of stories: a previously unknown story, a well-known fairy-tale (Cinderella), and a modified well-known fairy-tale (Little Red Riding Hood is not eaten by the wolf). The aim of our study was to test the hypothesis that in patients who tend to produce intrusions, over-learned information interferes with episodic recall, i.e., the retrieval of specific, unique past episodes. AD patients produced significantly more intrusions in the recall of the modified fairy-tale compared to the recall of the two other stories. Intrusions in the recall of the modified fairy-tale always consisted of elements of the original version of the story. We suggest that in AD patients intrusions may be traced back to the interfer- ence of strongly represented, over-learned information in episodic memory recall

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV <sub>1</sub> ), forced vital capacity (FVC), FEV <sub>1</sub> /FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years

Multicentric study underlining the interest of adding CD5, CD7 and CD56 expression assessment to the flow cytometric Ogata score in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Although numerous recent publications have demonstrated interest in multiparameter flow cytometry in the investigation of myelodysplastic disorders, it is perceived by many laboratory hematologists as difficult and expensive, requiring a high level of expertise. We report a multicentric open real-life study aimed at evaluating the added value of the technically simple flow cytometry score described by the Ogata group for the diagnosis of myelodysplastic syndromes. A total of 652 patients were recruited prospectively in four different centers: 346 myelodysplastic syndromes, 53 myelodysplastic/myeloproliferative neoplasms, and 253 controls. The Ogata score was assessed using CD45 and CD34 staining, with the addition of CD10 and CD19. Moreover, labeling of CD5, CD7 and CD56 for the evaluation of myeloid progenitors and monocytes was tested on a subset of 294 patients. On the whole series, the specificity of Ogata score reached 89%. Respective sensitivities were 54% for low-risk myelodysplastic syndromes, 68% and 84% for type 1 and type 2 refractory anemia with excess of blasts, and 72% for myelodysplastic/myeloproliferative neoplasms. CD5 expression was poorly informative. When adding CD56 or CD7 labeling to the Ogata score, sensitivity rose to 66% for low-risk myelodysplastic syndromes, to 89% for myelodysplastic/myeloproliferative neoplasms and to 97% for refractory anemia with excess of blasts. This large multicenter study confirms the feasibility of Ogata scoring in routine flow cytometry diagnosis but highlights its poor sensitivity in low-risk myelodysplastic syndromes. The addition of CD7 and CD56 in flow cytometry panels improves the sensitivity but more sophisticated panels would be more informative

The Effects of Uncertainty of Input Parameters on Nuclear Fuel Cycle Scenario Studies

International audienceNuclear systems, composed of reactors and fuel cycle facilities, are complex and in constant evolution. Fuel cycle scenario studies aim at evaluating the consequences of decisions taken in the near term on the eventual outcomes of a chosen fuel cycle.Scenario studies require a large amount of data and hypotheses, such as the energy demand and its evolution or the performances and characteristics of existing and future technologies. Each hypothesis, represented by a parameter, is a potential source of uncertainty that can impact the scenario outcomes. The Nuclear Energy Agency's Expert Group on Advanced Fuel Cycle Scenarios (NEA/AFCS) recently completed an activity that used sensitivity studies to evaluate the impact of uncertainty of the primary scenario input parameters on scenario results.At the beginning of the study, a base case scenario was specified and evaluated. It considers a PWR UOX reactor fleet using low enriched uranium oxide fuel and its gradual replacement by a sodium fast reactor (SFR) fleet using uranium/plutonium mixed oxide fuel. Each member of the group evaluated this scenario with its own scenario code (COSI, COSAC, FAMILY, SITON, TR_EVOL or VISION). It is noteworthy that the different codes show a good consistency in the results and that the differences have been investigated and documented in order to ensure a strong basis for comparison in the sensitivity study.Then, 17 key input parameters and their range of variation as well as 22 scenario outputs were identified and sensitivity analyses were conducted. The key parameters were chosen amongst the general assumptions on the scenario (energy demand, introduction date of fast reactor), reactors and facilities characteristics (burn-ups, losses at reprocessing) and some minor actinides recycling parameters. As far as possible, each parameter was varied independently from the others. This sensitivity study shows the relative impact of each parameter on each output metric. In order to compare the large amount of results, two methods of summarization were adopted, as described in the paper. These comparisons have shown that some parameters, such as the energetic production or the introduction date of fast reactors, have a strong impact on the results whereas others, like the UOX fabrication time, have almost no impact on the studied scenario

Respiratory muscle strength no influence the need for noninvasive ventilation after heart surgery

The aim of this study was to investigate the relation between preoperative respiratory muscle strength and indication and performance of noninvasive ventilation in the planned heart surgery. We conducted a retrospective study using data collected from clinical records and analyzed 109 medical records and noninvasive ventilation accompanying paper. We analyzed the values of respiratory muscle strength, peak flow and respirometry, as well as the postoperative respiratory complications, correlating them with indication and performance of the noninvasive ventilation. The t test was performed for continuous variables; the chi-square was used to investigate the influence of preoperative respiratory muscle strength values in the indication of noninvasive ventilation. Noninvasive ventilation was used in 32 (29%) subjects and the prime motive indication was hipercapy (44%). The successful use of noninvasive ventilation was observed in 94%. The decrease in preoperative strength, despite having a lower performance, showed no significant difference in relation to its use and outcome (p=0.73). The preoperative respiratory muscle strength was not able to provide for the use of noninvasive ventilation or its performance