Evolution of National Guidelines on Medicines Used to Treat COVID-19 in Pregnancy in 2020-2022: A Scoping Review.

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020-2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir-ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir-ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19

Predicting lymphoma in Sjögren's syndrome and the pathogenetic role of parotid microenvironment through precise parotid swelling recording

Objective: Parotid swelling (PSW) is a major predictor of non-Hodgkin lymphoma (NHL) in primary Sjögren's syndrome (pSS). However, since detailed information on the time of onset and duration of PSW is scarce, this was investigated to verify whether it may lead to further improved prediction. NHL localisation was concomitantly studied to evaluate the role of the parotid gland microenvironment in pSS-related lymphomagenesis. Methods: A multicentre study was conducted among patients with pSS who developed B cell NHL during follow-up and matched controls that did not develop NHL. The study focused on the history of salivary gland and lachrymal gland swelling, evaluated in detail at different times and for different durations, and on the localisation of NHL at onset. Results: PSW was significantly more frequent among the cases: at the time of first referred pSS symptoms before diagnosis, at diagnosis, and from pSS diagnosis to NHL. The duration of PSW was evaluated starting from pSS diagnosis, and the NHL risk increased from PSW of 2-12 months to > 12 months. NHL was prevalently localised in the parotid glands of the cases. Conclusion: A more precise clinical recording of PSW can improve lymphoma prediction in pSS. PSW as a very early symptom is a predictor, and a longer duration of PSW is associated with a higher risk of NHL. Since lymphoma usually localises in the parotid glands, and not in the other salivary or lachrymal glands, the parotid microenvironment appears to be involved in the whole history of pSS and related lymphomagenesis

Evolution of National Guidelines on Medicines Used to Treat COVID-19 in Pregnancy in 2020-2022: A Scoping Review

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020-2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir-ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir-ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19

Variations across Europe in hospitalization and management of pregnant women with SARS-CoV-2 during the initial phase of the pandemic : Multi-national population-based cohort study using the International Network of Obstetric Survey Systems (INOSS)

Funding Information: The national studies reported the following funding sources: The BOSS project was funded by the Belgian Federal Public Service of Health. The NOSS collaboration was supported by the Nordic Federation of Societies of Obstetrics and Gynecology (grant no. 6505, 2020). NOSS‐Denmark was supported by grants from The Region of Southern Denmark and Region Zealand's shared fund for joint health research projects (Reg. no. A767), and EasyTrial provided the data collection software. NOSS‐Finland received grants from the Finnish Medical Society, and from Helsinki University. UKOSS received funding from the National Institute for Health Research HS&DR Programme (11/46/12). The national studies in Italy and the Netherlands did not have specific funding. The multi‐national study received partial funding support from the European Medicines Agency (EMA) under the Framework service contract nr EMA/2018/28/PE. The content of this paper expresses the opinions of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or any of its committees or working parties. The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network, which is a public academic partnership coordinated by Utrecht University, the Netherlands. The CONSIGN project was scientifically coordinated by the University Medical Center, Utrecht. Funding Information: OB declares support from the European Medicines agency (EMA). HE declares grants from the Nordic Federation of Societies of Obstetrics and Gynecology (NFOG) and Norwegian Research Council (grant no 320181). AA declares a grant from the Region of Southern Denmark and Region Zealand's shared fund for joint health research projects. OA declares grants from the Finnish Medical Association and NFOG. MK declares grants from the National Institute for Health and Care Research, Medical Research Council, Healthcare Quality Improvement Partnership and Wellbeing of Women during the course of the study. MS leads a department that conducts studies on COVID‐19 vaccines for the European Medicines Agency, Pfizer, AstraZeneca and Janssen. All support was according to the ENCePP code of conduct. None of the other authors (NV, RR, SD, EJ, EO, MAS, TS, RV, AV, KB) has anything to disclose. Publisher Copyright: © 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).Introduction: The majority of data on COVID-19 in pregnancy are not from sound population-based active surveillance systems. Material and methods: We conducted a multi-national study of population-based national or regional prospective cohorts using standardized definitions within the International Network of Obstetric Survey systems (INOSS). From a source population of women giving birth between March 1 and August 31, 2020, we included pregnant women admitted to hospital with a positive SARS-CoV-2 PCR test ≤7 days prior to or during admission and up to 2 days after birth. The admissions were further categorized as COVID-19-related or non-COVID-19-related. The primary outcome of interest was incidence of COVID-19-related hospital admission. Secondary outcomes included severe maternal disease (ICU admission and mechanical ventilation) and COVID-19-directed medical treatment. Results: In a source population of 816 628 maternities, a total of 2338 pregnant women were admitted with SARS-CoV-2; among them 940 (40%) were COVID-19-related admissions. The pooled incidence estimate for COVID-19-related admission was 0.59 (95% confidence interval 0.27–1.02) per 1000 maternities, with notable heterogeneity across countries (I2 = 97.3%, P = 0.00). In the COVID-19 admission group, between 8% and 17% of the women were admitted to intensive care, and 5%–13% needed mechanical ventilation. Thromboprophylaxis was the most frequent treatment given during COVID-19-related admission (range 14%–55%). Among 908 infants born to women in the COVID-19-related admission group, 5 (0.6%) stillbirths were reported. Conclusions: During the initial months of the pandemic, we found substantial variations in incidence of COVID-19-related admissions in nine European countries. Few pregnant women received COVID-19-directed medical treatment. Several barriers to rapid surveillance were identified. Investment in robust surveillance should be prioritized to prepare for future pandemics.Peer reviewe

A Multicentric, Open-Label, Randomized, Comparative Clinical Trial of Two Different Doses of Expanded hBM-MSCs Plus Biomaterial versus Iliac Crest Autograft, for Bone Healing in Nonunions after Long Bone Fractures: Study Protocol

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n = 108) will be randomly assigned to either the experimental low dose (n = 36), the experimental high dose (n = 36), or the comparator arm (n = 36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe