Identification of Neural (N)-Cadherin as a Novel Endothelial Cell Receptor for Fibrin and Localization of the Complementary Binding Sites.

Based on the high structural homology between vascular endothelial (VE)-cadherin and neural (N)-cadherin, we hypothesized that fibrin, which is known to interact with VE-cadherin and promote angiogenesis through this interaction, may also interact with N-cadherin. To test this hypothesis, we prepared fibrin and its plasmin-produced and recombinant fragments covering practically all parts of the fibrin molecule. We also prepared the soluble extracellular portion of N-cadherin (sN-cadherin), which includes all five extracellular N-cadherin domains, and studied its interaction with fibrinogen, fibrin, and the aforementioned fibrin fragments using two independent methods, ELISA and SPR. The experiments confirmed our hypothesis, revealing that fibrin interacts with sN-cadherin with high affinity. Furthermore, the experiments localized the N-cadherin binding site within the fibrin ßN-domains. Notably, the recombinant dimeric (ß15-66)2 fragment, corresponding to these domains and mimicking their dimeric arrangement in fibrin, preserved the N-cadherin-binding properties of fibrin. To localize the fibrin binding site within N-cadherin, we performed ELISA and SPR experiments with (ß15-66)2 and recombinant N-cadherin fragments representing its individual extracellular domains and combinations thereof. The results obtained indicate that the interaction of fibrin with N-cadherin occurs through the third and fifth extracellular domains of the latter. This is in contrast to our previous study, which revealed that fibrin interacts only with the third extracellular domain of VE-cadherin. In conclusion, our study identified N-cadherin as a novel receptor for fibrin and localized complementary binding sites within both fibrin and N-cadherin. The pathophysiological role of this interaction remains to be established.

Maternal serum fructosamine levels and stillbirth: a case-control study of the Stillbirth Collaborative Research Network.

OBJECTIVE: To evaluate the association between maternal fructosamine levels at the time of delivery and stillbirth. DESIGN: Secondary analysis of a case-control study. SETTING: Multicentre study of five geographic catchment areas in the USA. POPULATION: All singleton stillbirths with known diabetes status and fructosamine measurement, and representative live birth controls. MAIN OUTCOME MEASURES: Fructosamine levels in stillbirths and live births among groups were adjusted for potential confounding factors, including diabetes. Optimal thresholds of fructosamine to discriminate stillbirth and live birth. RESULTS: A total of 529 women with a stillbirth and 1499 women with a live birth were included in the analysis. Mean fructosamine levels were significantly higher in women with a stillbirth than in women with a live birth after adjustment (177 ± 3.05 versus 165 ± 2.89 µmol/L, P < 0.001). The difference in fructosamine levels between stillbirths and live births was greater among women with diabetes (194 ± 8.54 versus 162 ± 3.21 µmol/L), compared with women without diabetes (171 ± 2.50 versus 162 ± 2.56 µmol/L). The area under the curve (AUC) for fructosamine level and stillbirth was 0.634 (0.605-0.663) overall, 0.713 (0.624-0.802) with diabetes and 0.625 (0.595-0.656) with no diabetes. CONCLUSIONS: Maternal fructosamine levels at the time of delivery were higher in women with stillbirth compared with women with live birth. Differences were substantial in women with diabetes, suggesting a potential benefit of glycaemic control in women with diabetes during pregnancy. The small differences noted in women without diabetes are not likely to justify routine screening in all cases of stillbirth. TWEETABLE ABSTRACT: Maternal serum fructosamine levels are higher in women with stillbirth than in women with live birth, especially in women with diabetes.

ACE inhibitors, angiotensin receptor blockers and endothelial injury in COVID-19.

BACKGROUND: COVID-19 is caused by the coronavirus SARS-CoV-2, which uses angiotensin-converting enzyme 2 (ACE-2) as a receptor for cellular entry. It is theorized that ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) may increase vulnerability to SARS-CoV-2 by upregulating ACE-2 expression, but ACE-I/ARB discontinuation is associated with clinical deterioration. OBJECTIVE: To determine whether ACE-I and ARB use is associated with acute kidney injury (AKI), macrovascular thrombosis and in-hospital mortality. METHODS: A retrospective, single-centre study of 558 hospital inpatients with confirmed COVID-19 admitted from 1 March to 30 April 2020, followed up until 24 May 2020. AKI and macrovascular thrombosis were primary end-points, and in-hospital mortality was a secondary end-point. RESULTS: AKI occurred in 126 (23.1%) patients, 34 (6.1%) developed macrovascular thrombi, and 200 (35.9%) died. Overlap propensity score-weighted analysis showed no significant effect of ACE-I/ARB use on the risk of occurrence of the specified end-points. On exploratory analysis, severe chronic kidney disease (CKD) increases odds of macrovascular thrombi (OR: 8.237, 95% CI: 1.689-40.181, P = 0.009). The risk of AKI increased with advancing age (OR: 1.028, 95% CI: 1.011-1.044, P = 0.001) and diabetes (OR: 1.675, 95% CI: 1.065-2.633, P = 0.025). Immunosuppression was associated with lower risk of AKI (OR: 0.160, 95% CI: 0.029-0.886, P = 0.036). Advancing age, dependence on care, male gender and eGFR < 60 mL min-1 /1.73 m2 increased odds of in-hospital mortality. CONCLUSION: We did not identify an association between ACE-I/ARB use and AKI, macrovascular thrombi or mortality. This supports the recommendations of the European and American Societies of Cardiology that ACE-Is and ARBs should not be discontinued during the COVID-19 pandemic.

Stillbirth and fetal anomalies: secondary analysis of a case-control study.

OBJECTIVE: Approximately 10% of stillbirths are attributed to fetal anomalies, but anomalies are also common in live births. We aimed to assess the relationship between anomalies, by system and stillbirth. DESIGN: Secondary analysis of a prospective, case-control study. SETTING: Multicentre, 59 hospitals in five regional catchment areas in the USA. POPULATION OR SAMPLE: All stillbirths and representative live birth controls. METHODS: Standardised postmortem examinations performed in stillbirths, medical record abstraction for stillbirths and live births. MAIN OUTCOME MEASURES: Incidence of major anomalies, by type, compared between stillbirths and live births with univariable and multivariable analyses using weighted analysis to account for study design and differential consent. RESULTS: Of 465 singleton stillbirths included, 23.4% had one or more major anomalies compared with 4.3% of 1871 live births. Having an anomaly increased the odds of stillbirth; an increasing number of anomalies was more highly associated with stillbirth. Regardless of organ system affected, the presence of an anomaly increased the odds of stillbirth. These relationships remained significant if stillbirths with known genetic abnormalities were excluded. After multivariable analyses, the adjusted odds ratio (aOR) of stillbirth for any anomaly was 4.33 (95% CI 2.80-6.70) and the systems most strongly associated with stillbirth were cystic hygroma (aOR 29.97, 95% CI 5.85-153.57), and thoracic (aOR16.18, 95% CI 4.30-60.94) and craniofacial (aOR 35.25, 95% CI 9.22-134.68) systems. CONCLUSIONS: In pregnancies affected by anomalies, the odds of stillbirth are higher with increasing numbers of anomalies. Anomalies of nearly any organ system increased the odds of stillbirth even when adjusting for gestational age and maternal race. TWEETABLE ABSTRACT: Stillbirth risk increases with anomalies of nearly any organ system and with number of anomalies seen.

Group-based physical activity interventions for postpartum women with children aged 0-5 years old: a systematic review of randomized controlled trials.

BACKGROUND: It is estimated that less than one third of women (28%) worldwide, are not sufficiently active, and there is evidence indicating physical activity (PA) participation is lower during pregnancy and the postpartum period. Despite the importance of educating and encouraging postpartum women to engage in PA, existing systematic reviews have only focused on examining the impact of individually tailored PA interventions and on specific postpartum populations such as women who are inactive (i.e., do not meet PA recommendations) or women at risk of gestational diabetes mellitus or postnatal depression. This review aims to fill this gap by examining the impact of group-based PA interventions on postpartum women's PA levels or other health behavior outcomes. METHODS: A systematic literature search was conducted using four electronic databases (MEDLINE, CINAHL, EMBASE and PsychInfo) of published studies between 1st January 2000 and 31st October 2020. Studies were included if they targeted postpartum women with no current health conditions, had children aged 0-5 years, and engaged postpartum women in a group-based PA program that reported PA or other health behavior outcomes. Out of a total of 1091 articles that were initially identified, six were included. RESULTS: Group-based PA interventions were moderately successful in changing or increasing postpartum women's self-reported PA levels and psychological wellbeing in the first 2 years of their offspring's life. Overall, group-based PA interventions were not successful in changing or increasing postpartum women's objectively measured PA levels, but only one study objectively measured postpartum women's PA levels. Narrative synthesis highlights the heterogeneity of the outcomes and methodologies used, and the low to medium risk of bias in the included studies. CONCLUSION: To strengthen the evidence-base for group-based PA programs with postpartum women there is an on-going need for more rigorous randomised controlled trials of appropriate length (at least 3 months in duration) with an adequate dose of group-based PA sessions per week (to meet PA guidelines), and that utilise objective measures of PA. In addition, future PA interventions for this population should include, at the very least, fidelity and process data to capture the characteristics or design features that appeal most to postpartum women.

The impact of respiratory protective equipment on difficult airway management: a randomised, crossover, simulation study.

The current international COVID-19 health crisis underlines the importance of adequate and suitable personal protective equipment for clinical staff during acute airway management. This study compares the impacts of standard air-purifying respirators and powered air-purifying respirators during simulated difficult airway scenarios. Twenty-five anaesthetists carried out four different standardised difficult intubation drills, either unprotected (control), or wearing a standard or a powered respirator. Treatment times and wearer comfort were determined and compared. In the wearer comfort evaluation form, operators rated mobility, noise, heat, vision and speech intelligibility. All anaesthetists accomplished the treatment objectives of all study arms without adverse events. Total mean (SD) intubation times for the four interventions did not show significant differences between the powered and the standard respirator groups, being 16.4 (8.6) vs. 19.2 (5.2) seconds with the Airtraq™; 11.4 (3.4) vs. 10.0 (2.1) seconds with the videolaryngoscope; 39.2 (4.5) vs. 40.1 (4.8) seconds with the fibreoptic bronchoscope scope; and 15.4 (5.7) vs. 15.1 (5.0) seconds for standard tracheal intubation by direct laryngoscopy, respectively. Videolaryngoscopy allowed the shortest intubation times regardless of the respiratory protective device used. Anaesthetists rated heat and vision significantly higher in the powered respirator group; however, noise levels were perceived to be significantly lower than in the standard respirator group. We conclude that standard and powered respirators do not significantly prolong simulated advanced intubation procedures.

Localization of a major susceptibility locus influencing preterm birth.

Preterm birth (PTB) is a complex trait, but little is known regarding its major genetic determinants. The objective of this study is to localize genes that influence susceptibility to PTB in Mexican Americans (MAs), a minority population in the USA, using predominantly microfilmed birth certificate-based data obtained from the San Antonio Family Birth Weight Study. Only 1302 singleton births from 288 families with information on PTB and significant covariates were considered for genetic analysis. PTB is defined as a childbirth that occurs at <37 completed weeks of gestation, and the prevalence of PTB in this sample was 6.4%. An ∼10 cM genetic map was used to conduct a genome-wide linkage analysis using the program SOLAR. The heritability of PTB was high (h(2) ± SE: 0.75 ± 0.20) and significant (P = 4.5 × 10(-5)), after adjusting for the significant effects of birthweight and birth order. We found significant evidence for linkage of PTB (LOD = 3.6; nominal P = 2.3 × 10(-5); empirical P = 1.0 × 10(-5)) on chromosome 18q between markers D18S1364 and D18S541. Several other chromosomal regions (2q, 9p, 16q and 20q) were also potentially linked with PTB. A strong positional candidate gene in the 18q linked region is SERPINB2 or PAI-2, a member of the plasminogen activator system that is associated with various reproductive processes. In conclusion, to our knowledge, perhaps for the first time in MAs or US populations, we have localized a major susceptibility locus for PTB on chromosome 18q21.33-q23.

Development of ELIP to Assess Physical Literacy for Emerging Adults: A Methodological and Epistemological Challenge.

Purpose: Following increased interest in physical literacy (PL), development of appropriate tools for assessment has become an important next step for its operationalization. To forward the development of such tools, the objective of this study was to build the foundations of the Évaluation de la Littératie Physique (ELIP), designed to help reduce existing tensions in approaches to PL assessment that may be resulting in a low uptake into applied settings. Methods: We followed two steps: (1) the development of the first version of ELIP by deploying a Delphi method (n = 30); and (2) the modification of items through cognitive interviews with emerging adults (n = 32). Results: The expert consensus highlighted four dimensions of PL to be assessed-physical; affective; cognitive; and social-with new perspectives, including a preference for broad motor tests over fitness. Conclusion: Results offer new insights into the assessment of emerging adults' PL, but ELIP still requires further work concerning validity, reliability, and sensitivity.

N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility.

The Wiskott-Aldrich syndrome protein (WASP) family of molecules integrates upstream signalling events with changes in the actin cytoskeleton. N-WASP has been implicated both in the formation of cell-surface projections (filopodia) required for cell movement and in the actin-based motility of intracellular pathogens. To examine N-WASP function we have used homologous recombination to inactivate the gene encoding murine N-WASP. Whereas N-WASP-deficient embryos survive beyond gastrulation and initiate organogenesis, they have marked developmental delay and die before embryonic day 12. N-WASP is not required for the actin-based movement of the intracellular pathogen Listeria but is absolutely required for the motility of Shigella and vaccinia virus. Despite these distinct defects in bacterial and viral motility, N-WASP-deficient fibroblasts spread by using lamellipodia and can protrude filopodia. These results imply a crucial and non-redundant role for N-WASP in murine embryogenesis and in the actin-based motility of certain pathogens but not in the general formation of actin-containing structures.