Validation of an Automated System for the Extraction of a Wide Dataset for Clinical Studies Aimed at Improving the Early Diagnosis of Candidemia

: There is increasing interest in assessing whether machine learning (ML) techniques could further improve the early diagnosis of candidemia among patients with a consistent clinical picture. The objective of the present study is to validate the accuracy of a system for the automated extraction from a hospital laboratory software of a large number of features from candidemia and/or bacteremia episodes as the first phase of the AUTO-CAND project. The manual validation was performed on a representative and randomly extracted subset of episodes of candidemia and/or bacteremia. The manual validation of the random extraction of 381 episodes of candidemia and/or bacteremia, with automated organization in structured features of laboratory and microbiological data resulted in ≥99% correct extractions (with confidence interval < ±1%) for all variables. The final automatically extracted dataset consisted of 1338 episodes of candidemia (8%), 14,112 episodes of bacteremia (90%), and 302 episodes of mixed candidemia/bacteremia (2%). The final dataset will serve to assess the performance of different ML models for the early diagnosis of candidemia in the second phase of the AUTO-CAND project

Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy.

Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they respond differentially to the stimulation of ER-phagy is unknown. Here, we describe an activation mechanism unique to FAM134C during starvation. In fed conditions, FAM134C is phosphorylated by casein kinase 2 (CK2) at critical residues flanking the LIR domain. Phosphorylation of these residues negatively affects binding affinity to the autophagy proteins LC3. During starvation, mTORC1 inhibition limits FAM134C phosphorylation by CK2, hence promoting receptor activation and ER-phagy. Using a novel tool to study ER-phagy in vivo and FAM134C knockout mice, we demonstrated the physiological relevance of FAM134C phosphorylation during starvation-induced ER-phagy in liver lipid metabolism. These data provide a mechanistic insight into ER-phagy regulation and an example of autophagy selectivity during starvation.We thank G. Diez Roux and P. Ashley-Norman for critical reading of the manuscript. We thank the microscopy, MS, advanced histopathology, and FACS facilities at TIGEM Institute. We thank E. Nusco for helping us with AAV injections. Funding: This work was supported by European Research Council (ERC) (714551), Telethon intramural grants, and Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 2015 Id 17717) (to C.S.) and Telethon Foundation (TMPGCBX16TT), AFM Telethon (Trampoline Grant), and AIRC (MFAG-2020-24856) (to P.G.). G.D.L. is a recipient of AIRC fellowship “Francesco Alicino” (25407). V.L. acknowledges funding from the ERC (101001784), the Italian MIUR-PRIN 2017 (2017FJZZRC), and the Swiss National Supercomputing Center (CSCS) (project ID u8). The work of A.S. was supported by the German Research Foundation DFG (SFB1177/2 and WO210/20-2) and the Dr. Rolf M. Schwiete Stiftung (13/2017). A.E. is supported by the RETOS projects Programme of Spanish Ministry of Science, Innovation and Universities, Spanish State Research Agency (grants SAF2015-67538-R and PID2019-104012RB-I00), and the ERC (638891). A.B.P.-G. is a recipient of Ph.D. fellowship from MICIU/AEI (BES-2017-081381). A.R. is a recipient of Umberto Veronesi Foundation postdoctoral fellowship. Author contributions: G.D.L. and F.I. performed most of the experiments. F.I. and A.B.P.-G. performed in vivo experiments. M.M. performed mutagenesis experiments. S.A. and V.L. performed LC3-FAM134C binding analysis. C.P.Q.M. performed in vitro phosphorylation assays. L.C. analyzed CK2 substrate phosphorylation. F.S., A.P., C.C., and A.S. analyzed proteomic data. G.N. provided critical suggestions. A.R. performed proteomic experiments. A.E. supervised in vivo experiments. M.R., L.A.P., and O.M. supervised CK2 experiments. C.S. designed the study. P.G. and C.S. conceived and supervised the experiments. C.S., P.G., V.L., and M.R. wrote the paper. G.D.L. and F.I. prepared the figures. All the authors read the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.S

Search of somatic GATA4 and NKX2.5 gene mutations in sporadic septal heart defects

Q3Q1Reporte de caso306-309High prevalence of somatic mutations in the cardiac transcription factor genes NKX2.5 and GATA4 have been reported in the affected cardiovascular tissue of patients with isolated cardiac septal defects, suggesting a role of somatic mutations in the pathogenesis of these congenital heart defects (CHDs). However, all somatic mutations have been identified in DNA extracted from an archive of formalin-fixed cardiac tissues. In the present study, to address the hypothesis that somatic mutations are important in isolated CHDs, we analyzed the GATA4 and NKX2.5 genes in the fresh-frozen pathologic cardiac tissue specimen and corresponding non-diseased tissue obtained from a series of 62 CHD patients, including 35 patients with cardiac septal defects and 27 with other cardiac anomalies. We identified one variant and two common polymorphisms in the NKX2.5 gene, and six variants and two common polymorphisms in the GATA4 gene. All identified variants were seen in both the fresh-frozen pathologic cardiac tissue and the corresponding non-diseased tissue, which indicates that they all were constitutional variants. The present study has identified NKX2.5 and GATA4 constitutional variants in our CHD cohort, but was unable to replicate the previously published findings of high prevalence of somatically derived sequence mutations in patients with cardiac septal defects using fresh-frozen cardiac tissues rather than formalin-fixed tissues. (C) 2011 Elsevier Masson SAS. All rights reserved

The T.O.S.CA. Project: Research, Education and Care

Despite recent and exponential improvements in diagnostic- therapeutic pathways, an existing “GAP” has been revealed between the “real world care” and the “optimal care” of patients with chronic heart failure (CHF). We present the T.O.S.CA. Project (Trattamento Ormonale dello Scompenso CArdiaco), an Italian multicenter initiative involving different health care professionals and services aiming to explore the CHF “metabolic pathophysiological model” and to improve the quality of care of HF patients through research and continuing medical education

MOLNUPIRAVIR COMPARED TO NIRMATRELVIR/RITONAVIR FOR COVID-19 IN HIGH-RISK PATIENTS WITH HAEMATOLOGICAL MALIGNANCY IN EUROPE. A MATCHED-PAIRED ANALYSIS FROM THE EPICOVIDEHA REGISTRY

Introduction: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections, which reduce both hospitalization and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, while molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir, because it displays less frequent drug-drug interactions and contraindications. A caveat connected to molnupiravir derives from the mode of action inducing viral mutations. In clinical trials on patients without haematological malignancy, mortality rate reduction of molnupiravir appeared less pronounced than that of nirmatrelvir/ritonavir. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, we here assess the effectiveness of molnupiravir compared to nirmatrelvir/ritonavir in our cohort of patients with haematological malignancies. Methods: Clinical data of patients treated either with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and baseline haematological malignancy severity to controls treated with nirmatrelvir/ritonavir. Results: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (IQR 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 57% (n=66) of the patients had controlled baseline haematological malignancy, 13% (n=15) stable, and 30% (n=35) had active disease at COVID-19 onset in each of the groups. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of vaccinated patients was observed in both groups (molnupiravir n=77, 66% vs nirmatrelvir/ritonavir n=87, 75%), those treated with nirmatrelvir/ritonavir had more often received four doses (n=27, 23%) as compared to patients treated with molnupiravir (n=5, 4%, p<0.001). No differences were detected in COVID-19 severity (p=0.39) or hospitalization (p=1.0). No statistically significant differences were identified in overall mortality rate (p=0.78) or in survival probability (d30 p=0.19, d60 p=0.67, d90 p=0.68, last day of follow up p=0.68). In all patients, deaths were either attributed to COVID-19 or the infection contributed to death as per treating physician's judgement. Conclusions: In high-risk patients with haematological malignancies and COVID-19, molnupiravir showed rates of hospitalization and mortality comparable to those of nirmatrelvir/ritonavir in this matched-pair analysis. Molnupiravir appears to be a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy

Age, Successive Waves, Immunization, and Mortality in Elderly COVID-19 Haematological Patients: EPICOVIDEHA Findings

Introduction: elderly patients with haematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection impact in different age groups remains unstudied in detail. Methods: We analysed elderly patients (age groups: 65-70, 71-75, 76-80 and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with haematological malignancy. results: the study included data from 3,603 elderly patients (aged 65 or older) with haematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves.tThe 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukaemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusions: These data underscore the heterogeneity of elderly haematological patients, highlight the different impact of COVID waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts

Towards the recommendation of resources in Coursera

Technology Enhanced Learning (TEL) largely focuses on the retrieval and reuse of educational resources from Web platforms like Coursera. Unfortunately, Coursera does not provide educational metadata of its content. To overcome this limitation, this study proposes a data mining approach for discovering Teaching Contexts (TC) where resources have been delivered in. Such TCs can facilitate the retrieval of resources for the teaching preferences and requirements of teachers

Enhancing categorization of learning resources in the DAtaset of joint educational entities

The DAtaset of Joint Educational Entities (DAJEE) is a repository which hosts more than 20,000 educational resources crawled from the MOOC platform Coursera. The resources are divided per category according to the MOOC categorization on Coursera, which is, however, very shallow. This contribution focuses on a more meaningful categorization of the resources in DAJEE, tailored to their content. To achieve such goal, our approach enriches the resources in DAJEE with semantic entities by applying state-of-the-art semantic techniques. The result is a significant improvement of the categorization of the resources in DAJEE than the previous version

Enrichment of the Dataset of Joint Educational Entities with the Web of Data

The public availability of datasets of teaching resources is an issue for the design, development and evaluation of Information Retrieval and Recommender Systems in Technology Enhanced Learning. Recently, the Dataset of Joint Educational Entities (DAJEE) has provided the community with a very exhaustive collection of resources coming from Massive Open Online Courses. This work proposes a representation of the DAJEE dataset according to Linked Data principles, interlinking the large amount of resources in DAJEE with the Web of Data. The transcript of the educational resources in DAJEE have been annotated through a Named Entity Recognition tool in order to create interlinks with the DBpedia entities. The DBpedia knowledge base provides additional information related to categories, that can be exploited to infer new knowledge and support reasoning processes