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BACKGROUND: The COVID-19 pandemic has been associated with worsened metabolic and mental health in the general and perinatal population. The postpartum is a critical moment regarding these outcomes particularly in women with gestational diabetes mellitus (GDM). We investigated the cardio-metabolic and mental health outcomes before and during the pandemic in this population. METHODS: This cohort study included 418 women with GDM, recruited during two distinct periods. This included 180 women exposed to the pandemic (E+) and recruited between May 2020-April 2021 and 238 women who were not exposed to the pandemic during their postpartum period (attended a year before=non-exposed (E-)) and recruited between January-December 2019. Among the E+, a nested-subcohort of 120 women were exposed both during pregnancy and postpartum. During the pandemic, we adopted a hybrid follow-up of women that consisted of in-person consultations, regular contact via phone calls (35%), sent recorded exercise guide to patients to follow at home and linked to our website. We specifically focused on maintaining motivation and keeping a strong focus on healthy lifestyle behaviors. Obstetric, neonatal, cardio-metabolic and mental health outcomes were assessed during pregnancy and postpartum. RESULTS: The pandemic was not associated with worsened weight, weight retention, glucose tolerance, metabolic syndrome, well-being or depression in the postpartum with the exception of a minimally increased HbA1c, diastolic blood pressure and lower emotional eating scores in E+ women (all p ≤ 0.046). In the nested subcohort, E+ women had a slightly increased HbA1c at the first GDM visit and a higher need for glucose-lowering medication (both p ≤ 0.014), but HbA1c at the end of pregnancy and other cardio-metabolic, mental health, obstetric and neonatal outcomes during pregnancy were similar. CONCLUSIONS: The pandemic was not associated with any clinically relevant worsening of cardio-metabolic, mental health, obstetrical and neonatal outcomes in our GDM cohort. This was possibly due to a continued hybrid follow-up, and the partial lockdown in Switzerland. ispartof: FRONTIERS IN ENDOCRINOLOGY vol:13 ispartof: location:Switzerland status: published

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

Senescent cells accumulate in aging tissues, and their elimination can favor healthy aging1-4. Therefore, therapeutic interventions targeting cellular senescence may be promising strategies for delaying or reversing a vast range of age-related diseases5. As cells of the immune system are responsible for senescent cell elimination6-11, a possible anti-aging and pro-healthspan treatment is the specific activation of the immune system to induce senescent cell clearance. However, whether this elimination is limited by an immune checkpoint leading to tolerance of senescence cells is currently unknown. Here, we show that cellular senescence, elicited by various stressors other than oncogenic activation, triggers immune escape toward natural killer (NK) cells, which may thus limit the use of anti-senescence immunotherapies. Moreover, using mass spectrometry, we reveal that senescent cells reshuffle their glycosphingosine composition, toward a marked increase in the ganglioside content, including the appearance of disialylated ganglioside GD3. This senescence associated GD3 overexpression results from transcriptional upregulation of the gene encoding the enzyme ST8SIA1, which is responsible for GD3 synthesis. The high level of GD3 leads to a strong immunosuppressive signal affecting NK cell-mediated immunosurveillance. In a mouse model of lung fibrosis, senescent cell-dependent NK cell immunosuppression is blunted by in vivo administration of anti-GD3 monoclonal antibodies leading to a clear anti-fibrotic effect. These results demonstrate that GD3 upregulation in senescent cells drives a switch from immune clearance toward immune tolerance of senescent cells. Therefore, we propose that GD3 level acts as a senescence-associated immune checkpoint (SIC) that regulates NK cell functions toward senescent cells. Thus, targeting GD3 with specific antibodies may be a promising strategy for the development of effective anti-senescence immunotherapies.