SARS-CoV-2 infection in pregnancy in Denmark - characteristics and outcomes after confirmed infection in pregnancy: a nationwide, prospective, population-based cohort study

IntroductionAssessing the risk factors for and consequences of infection with SARS-CoV-2 during pregnancy is essential to guide clinical guidelines and care. Previous studies on the influence of SARS-CoV-2 infection in pregnancy have been among hospitalised patients, which may have exaggerated risk estimates of severe outcomes because all cases of SARS-CoV-2 infection in the pregnant population were not included. The objectives of this study were to identify risk factors for and outcomes after SARS-CoV-2 infection in pregnancy independent of severity of infection in a universally tested population, and to identify risk factors for and outcomes after severe infection requiring hospital admission. Material and MethodsThis was a prospective population-based cohort study in Denmark using data from the Danish National Patient Register and Danish Microbiology Database and prospectively registered data from medical records. We included all pregnancies between March 1 and October 31, 2020 and compared women with a positive SARS-CoV-2 test during pregnancy to non-infected pregnant women. Cases of SARS-CoV-2 infection in pregnancy were both identified prospectively and through register linkage to secure that all cases were identified and that cases were pregnant during infection. Main outcome measures were pregnancy, delivery, maternal, and neonatal outcomes. Severe infection was defined as hospital admission due to COVID-19. ResultsAmong 82 682 pregnancies, 418 women had SARS-CoV-2 infection during pregnancy, corresponding to an incidence of 5.1 per 1000 pregnancies, 23 (5.5%) of which required hospital admission due to COVID-19. Risk factors for infection were asthma (OR 2.19 [1.41-3.41]) and being foreign born (OR 2.12 [1.70-2.64]). Risk factors for hospital admission due to COVID-19 included obesity (OR 2.74 [1.00-7.51]), smoking (OR 4.69 [1.58-13.90]), infection after gestational age (GA) 22 weeks (GA 22-27 weeks: OR 3.77 [1.16-12.29]; GA 28-36 weeks: OR 4.76 [1.60-14.12]) and having asthma (OR 4.53 [1.39-14.79]). We found no difference in any obstetric or neonatal outcomes. ConclusionsOnly 1 in 20 women with SARS-CoV-2 infection during pregnancy require admission to hospital due to COVID-19. And severe outcomes of SARS-CoV-2 infection in pregnancy are rare. Key MessagePopulation based cohort study about SARS-CoV-2 infection during pregnancy. Asthma and foreign ethnicity were identified as risk factors for infection while obstetric outcomes did not change. Obesity, smoking, infection after GA 22, and asthma increased the risk of hospital admission.

Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease: A Nationwide, Long-Time, Prospective Follow-Up.

BACKGROUND: Fabry disease is a rare metabolic glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A--leading to cellular accumulation of globotriasylceramide in different organs, vessels, tissues, and nerves. The disease is associated with an increased risk of cerebrovascular disease at a young age in addition to heart and kidney failure. OBJECTIVE: The objective of this study was to assess brain function and structure in the Danish cohort of patients with Fabry disease in a prospective way using 18-fluoro-deoxyglucose (F-18 FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI). PATIENTS: Forty patients with Fabry disease (14 males, 26 females, age at inclusion: 10-66 years, median: 39 years) underwent a brain F-18-FDG-PET-scan at inclusion, and 31 patients were followed with FDG-PET biannually for up to seven years. All patients (except one) had a brain MRI-scan at inclusion, and 34 patients were followed with MRI biannually for up to nine years. IMAGE ANALYSIS: The FDG-PET-images were inspected visually and analysed using a quantitative 3-dimensional stereotactic surface projection analysis (Neurostat). MRI images were also inspected visually and severity of white matter lesions (WMLs) was graded using a visual rating scale. RESULTS: In 28 patients brain-FDG-PET was normal; in 23 of these 28 patients brain MRI was normal--of the remaining five patients in this group, four patients had WMLs and one patient never had an MRI-scan. In 10 patients hypometabolic areas were observed on brain-FDG-PET; all of these patients had cerebral infarcts/hemorrhages visualized on MRI corresponding to the main hypometabolic areas. In two patients brain-FDG-PET was ambiguous, while MRI was normal in one and abnormal in the other. CONCLUSION: Our data indicated that, in patients with Fabry disease, MRI is the preferable clinical modality--if applicable--when monitoring cerebral status, as no additional major brain-pathology was detected with FDG-PET.

A comparison of oxycodone prolonged-release vs. oxycodone + naloxone prolonged-release after laparoscopic hysterectomy.

BACKGROUND: Targiniq®, an oxycodone prolonged-release (PR) formulation combined with the opioid antagonist naloxone PR, aims to prevent opioid-induced constipation without impairing the analgesic efficacy. This has been confirmed during prolonged use in chronic pain or cancer patients. The purpose of our study was to compare clinical effects of oxycodone PR with oxycodone PR + naloxone PR for short-term post-operative pain management. METHODS: This randomised, double-blind, prospective study included 85 women undergoing laparoscopic hysterectomy. The two groups received either oxycodone PR 10 mg or oxycodone PR 10 mg + naloxone PR 5 mg as pre-medication and twice daily for 3 days. As rescue analgesic, the patients received oxycodone intravenous during the first 24 h post-operatively and oxycodone tablets in the 24-72-h period. Constipation, other side effects, pain and satisfaction were registered during the first 7 post-operative days. RESULTS: Demographic, pre- and perioperative variables and the use of rescue analgesics were similar in the groups. There were no significant differences in variables related to constipation. In the oxycodone PR + naloxone PR group, 25% had no defecation during the first 72 h post-operatively, compared with 20% in the oxycodone PR group (mean 1.2 ± 1.1 vs. 2.1 ± 2.4 defecations). Other opioid-induced effects and side effects showed no significant differences. Only 7% were dissatisfied with their oral pain treatment. CONCLUSION: Addition of naloxone to oxycodone PR tablets in a pain regimen administered twice daily the first three post-operative days had no significant clinical effects on constipation or other variables during the first week after hysterectomy.

Isoform-specific expression of VEGF-B in normal tissues and tumors.

Vascular endothelial growth factor B (VEGF-B), a member of the VEGF/PDGF family, is highly expressed in many tissues with two differentially spliced transcripts generating two secreted isoforms, VEGF-B167 and VEGF-B186. In this work, we have investigated the expression of VEGF-B in tissues and cell lines using techniques that can distinguish the two isoforms. The results showed that the VEGF-B167 isoform was predominantly expressed in most tissues, accounting for more than 80% of the total VEGF-B transcripts. The VEGF-B186 isoform was expressed at lower levels and only in a limited number of tissues. Moreover, the VEGF-B186 isoform was up-regulated in mouse and human tumor cell lines and primary tumors compared with their corresponding normal tissues. Taken together, our data suggest a fine genetic control of the expression of the two isoforms of VEGF-B, implying tissue- and cell-specific roles of the two VEGF-B isoforms.

Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect.

BACKGROUND: Vascular endothelial growth factors (VEGFs) and their receptors are essential regulators of vasculogenesis and angiogenesis in both embryos and adults. One of the factors with a still unknown physiological function is VEGF-B, which is expressed in many tissues, including the heart. METHODS AND RESULTS: Mice carrying a targeted deletion in the VEGF-B gene were developed. In VEGF-B(-/-) animals, no gross abnormalities were observed in organs that normally show high expression of VEGF-B, such as the heart, muscle, and kidney. Analysis of heart function by ECG showed that adult VEGF-B(-/-) mice have an atrial conduction abnormality characterized by a prolonged PQ interval. VEGF- or basic fibroblast growth factor-induced corneal angiogenesis was similar in normal and VEGF-B(-/-) mice. CONCLUSIONS: VEGF-B seems to be required for normal heart function in adult animals but is not required for proper development of the cardiovascular system either during development or for angiogenesis in adults.

PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor.

Platelet-derived growth factors (PDGFs) are important in many types of mesenchymal cell. Here we identify a new PDGF, PDGF-C, which binds to and activates the PDGF alpha-receptor. PDGF-C is activated by proteolysis and induces proliferation of fibroblasts when overexpressed in transgenic mice. In situ hybridization analysis in the murine embryonic kidney shows preferential expression of PDGF-C messenger RNA in the metanephric mesenchyme during epithelial conversion. Analysis of kidneys lacking the PDGF alpha-receptor shows selective loss of mesenchymal cells adjacent to sites of expression of PDGF-C mRNA; this is not found in kidneys from animals lacking PDGF-A or both PDGF-A and PDGF-B, indicating that PDGF-C may have a unique function.

Comparison of usefulness of estradiol vaginal tablets and estriol vagitories for treatment of vaginal atrophy.

BACKGROUND: Atrophic vaginitis is a common condition. This study compared the usefulness of estradiol vaginal tablets (EVT) and estriol vagitories (EV) in treatment of atrophic vaginitis. METHODS: Ninety-six postmenopausal women with symptoms of atrophic vaginitis were treated for 24 weeks with either EVT or with EV. Patients used the medication daily for the first 2 weeks of the study, and twice-weekly thereafter. RESULTS: Both EVT and EV were effective in treating vaginal atrophy and patients in both treatment groups experienced a significant improvement in vaginal symptoms such as itching, irritation, dryness, and dyspareunia. At the end of the study three (6%) EVT treated women reported leakage and none needed to use sanitary towels. Among the EV treated women 31 (65%) reported leakage and 14 (29%) required sanitary protection. Furthermore, 90% in the EVT group perceived the medication as hygienic compared to 79% in the EV group, and 49% in the EVT group indicated that the product was easy to use compared to 28% in the EV group. Endometrial thickness was increased (1.1 mm with EVT and 0.5 mm on EV) in both treatment groups during the first 2 weeks of the study, but returned to baseline levels when the frequency of drug application was reduced to twice-weekly. CONCLUSIONS: Estradiol vaginal tablets provides an effective alternative to traditional forms of local estrogen therapy.

Localization of VEGF-B in the mouse embryo suggests a paracrine role of the growth factor in the developing vasculature.

Vascular endothelial growth factor B (VEGF-B) is structurally closely related to VEGF and binds one of its receptors, VEGFR-1. In situ hybridization and immunohistochemistry were used to localize VEGF-B mRNA and protein in embryonic mouse tissues. In 8.5-17.5 day embryos, VEGF-B was most prominently expressed in the developing myocardium, but not in the cardiac cushion tissue. The strong expression in the heart persisted at later developmental stages, while weaker signals were obtained from several other tissues, including developing muscle, bone, pancreas, adrenal gland, and from the smooth muscle cell layer of several larger vessels, but not from endothelial cells. VEGF-B is likely to act in a paracrine fashion, as its receptor is almost exclusively present in endothelial cells. VEGF-B may have a role in vascularization of the heart, skeletal muscles and developing bones, and in paracrine interactions between endothelial and surrounding muscle cells.

Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells.

The vascular endothelial growth factor (VEGF) family has recently expanded by the identification and cloning of three additional members, namely VEGF-B, VEGF-C, and VEGF-D. In this study we demonstrate that VEGF-B binds selectively to VEGF receptor-1/Flt-1. This binding can be blocked by excess VEGF, indicating that the interaction sites on the receptor are at least partially overlapping. Mutating the putative VEGF receptor-1/Flt-1 binding determinants Asp63, Asp64, and Glu67 to alanine residues in VEGF-B reduced the affinity to VEGF receptor-1 but did not abolish binding. Mutational analysis of conserved cysteines contributing to VEGF-B dimer formation suggest a structural conservation with VEGF and platelet-derived growth factor. Proteolytic processing of the 60-kDa VEGF-B186 dimer results in a 34-kDa dimer containing the receptor-binding epitopes. The binding of VEGF-B to its receptor on endothelial cells leads to increased expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1, suggesting a role for VEGF-B in the regulation of extracellular matrix degradation, cell adhesion, and migration.

Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors.

The growth of solid tumors is dependent on angiogenesis, the formation of new blood vessels. Vascular endothelial growth factor (VEGF) is a secreted endothelial-cell-specific mitogen. We have recently characterized two novel endothelial growth factors with structural homology to VEGF and named them VEGF-B and VEGF-C. To further define the roles of VEGF-B and VEGF-C, we have studied their expression in a variety of human tumors, both malignant and benign. VEGF-B mRNA was detected in most of the tumor samples studied, and the mRNA and the protein product were localized to tumor cells. Endothelial cells of tumor vessels were also immunoreactive for VEGF-B, probably representing the binding sites of the VEGF-B polypeptide secreted by adjacent tumor cells. VEGF-C mRNA was detected in approximately one-half of the cancers analyzed. Via in situ hybridization, VEGF-C mRNA was also localized to tumor cells. All lymphomas studied contained low levels of VEGF-C mRNA, possibly reflecting the cell-specific pattern of expression of the VEGF-C gene in the corresponding normal cells. The expression of VEGF-C is associated with the development of lymphatic vessels, and VEGF-C could be an important factor regulating the mutual paracrine relationships between tumor cells and lymphatic endothelial cells. Furthermore, VEGF-C and VEGF-B can, similarly to VEGF, be involved in tumor angiogenesis.