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BackgroundWe aim to evaluate whether fertility, pregnancy, delivery and breastfeeding have been actually improving in women with multiple sclerosis (MS), compared with general population, and in relation to treatment features.MethodsWe included 2018–2020 population-level healthcare data on women with MS living in the Campania region (Italy). Fertility, pregnancy and delivery outcomes were obtained from Certificate of Delivery Assistance; breastfeeding was collected up to 6 months after delivery by trained personnel.ResultsOut of 2748 women with MS in childbearing age, 151 women delivered 156 babies. Fertility rate was 0.58 live births per woman with MS, compared with 1.29 in Campania region and 1.25 in Italy. Disease-modifying treatment (DMT) continuation during pregnancy was associated with lower birth weight (coeff −107.09; 95% CI –207.91 to –6.26; p=0.03). Exposure to DMTs with unknown/negative effects on pregnancy was associated with birth defects (OR 8.88; 95% CI 1.35 to 58.41; p=0.02). Birth defects occurred in pregnancies exposed to dimethyl fumarate (2/21 exposed pregnancies), fingolimod (1/11 exposed pregnancies) and natalizumab (2/30 exposed pregnancies). After delivery, 18.8% of women with MS were escalated of DMT efficacy, while 50.7% started on same/similar-efficacy DMTs, and 30.5% did not receive DMT. The probability of breastfeeding was higher in women who were treated with breastfeeding-safe DMTs (OR 5.57; 95% CI 1.09 to 28.55; p=0.03).ConclusionsFertility rate in women with MS remains below the general population. Family planning and subsequent DMT decisions should aim to achieve successful pregnancy, delivery and breastfeeding outcomes, while controlling disease activity.

ABSTRACTAcute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease.We performed an epigenome-wide analysis of circulating CD4+and CD8+T cells isolated from ACS patients and healthy subjects (HS), enrolled in the DIANA clinical trial, by reduced-representation bisulphite sequencing (RRBS). In CD4+T cells, we identified 61 differentially methylated regions (DMRs) associated with 57 annotated genes (53% hyper- and 47% hypo-methylated) by comparing ACS patients vsHS. In CD8+T cells, we identified 613 DMRs associated with 569 annotated genes (28% hyper- and 72% hypo-methylated) in ACS patients as compared to HS. In CD4+vsCD8+T cells of ACS patients we identified 175 statistically significant DMRs associated with 157 annotated genes (41% hyper- and 59% hypo-methylated). From pathway analyses, we selected six differentially methylated hub genes (NFATC1, TCF7, PDGFA, PRKCB, PRKCZ, ABCA1) and assessed their expression levels by q-RT-PCR. We found an up-regulation of selected genes in ACS patients vsHS (P< 0.001). ABCA1, TCF7, PDGFA,and PRKCZgene expression was positively associated with CK-MB serum concentrations (r= 0.75, P= 0.03; r= 0.760, P= 0.029; r= 0.72, P= 0.044; r= 0.74, P= 0.035, respectively).This pilot study is the first single-base resolution map of DNA methylome by RRBS in CD4+and CD8+T cells and provides specific methylation signatures to clarify the role of aberrant methylation in ACS pathogenesis, thus supporting future research for novel epigenetic-sensitive biomarkers in the prevention and early diagnosis of this pathology.

The frictional velocity dependence and healing behavior of subduction fault zones play key roles in the nucleation of stick‐slip instabilities at convergent margins. Diagenetic to low‐grade metamorphic processes such as pressure solution are proposed to be responsible for the change in frictional properties of fault materials along plate interfaces; pressure solution also likely contributes to the acceleration of healing according to previous studies. Here, we report friction studies for temperatures of 20–100°C and normal stresses from 20 to 125 MPa on samples collected from ancient subduction fault zones, the Lower Mugi and Makimine mélanges of the Cretaceous Shimanto belt. The two mélanges correspond to the updip and downdip limits of the seismogenic zone and include deformation features that indicate lower and higher degrees of pressure solution. Our data show that the Lower Mugi mélange exhibits velocity‐weakening to velocity‐neutral frictional behavior under low normal stress and that the Makimine mélange sample shows velocity‐strengthening behavior under high normal stress. We suggest that mineralogical changes due to diagenesis and metamorphism influence fault slip behavior. We measure frictional healing in slide‐hold‐slide experiments for the Lower Mugi mélange sample and document the role of pressure solution in fault healing. Our results show that frictional healing increases at higher temperatures. The microstructures related to pressure solution found in the post‐experimental gouges support the idea that the enhanced healing is related to pressure solution. Investigating the mechanical properties of rock materials in plate boundary faults is crucial for the understanding of subduction zone earthquakes. The nucleation of earthquakes along the plate boundary occurs in a zone where friction drops during slip and fault strength rebuilds after an earthquake. The mechanical properties of fault materials in this zone are likely influenced by local diffusion of mobile elements during the interseismic period. Here, we perform friction experiments using two samples of ancient plate boundary faults that were near the updip and downdip limits of the zone, respectively. The first set of experiments reveals a variation in frictional response to slip under an experimental setup analogous to subduction zone conditions. Variation in the magnitude of interseismic pressure solution strain preserved in the samples is likely the cause of varying responses that lead to the nucleation and cessation of earthquakes. We conduct another series of experiments under varying hydrothermal conditions that reveal a faster restrengthening of the fault material at elevated temperatures. This is likely related to the temperature dependence of pressure solution, which is found to be an operative deformation mechanism based on the examination of post‐experimental materials. Mélanges bounding the upper and lower limits of the seismogenic zone show changes in frictional velocity‐dependence with normal stressMicrostructures of the sheared samples suggest that temperature dependence of healing occurs via diffusive mass transferThermally‐activated deformation mechanisms can modulate frictional velocity‐dependence and healing behavior of plate boundary faults Mélanges bounding the upper and lower limits of the seismogenic zone show changes in frictional velocity‐dependence with normal stress Microstructures of the sheared samples suggest that temperature dependence of healing occurs via diffusive mass transfer Thermally‐activated deformation mechanisms can modulate frictional velocity‐dependence and healing behavior of plate boundary faults