Homelessness in pregnancy.

OBJECTIVES: To evaluate the association, if any, of homelessness or refuge accommodation on delivery and short term perinatal outcomes in an Irish tertiary maternity hospital. METHODS: A retrospective cohort study of 133 singleton pregnancies in women reporting to be homeless or living in refuge at their booking antenatal appointment between 2013 and 2022. Analysis compared sociodemographic characteristics and perinatal outcomes in this cohort to a reference population of 76,858 women with stable living arrangements. RESULTS: Women in the homeless/refuge population were statistically more likely to be single (75.2 % vs 39.5 %, p < 0.001), have an unplanned pregnancy (73.7 % vs 27.2 %, p < 0.001), report a history of psychiatric illness (42.9 % vs 22.4 %, p < 0.001), domestic violence (18.8 % vs 0.9 %, p < 0.001) alcohol consumption in pregnancy (3.0 % vs 0.8 %, p < 0.001) or smoking in pregnancy (41.3 % vs 9.7 %, p < 0.001). They were significantly more likely to have a preterm birth (adjusted OR 1.71 (1.01-2.87) p = 0.04). They also had a significantly lower median birth weight compared to the reference population (birthweight 3270 g vs 3420 g, p < 0.001). CONCLUSION: Women in the homeless and refuge population are more likely to experience poorer perinatal outcomes compared to women with stable living arrangements.

The duration of labor in spontaneous preterm deliveries: A retrospective observational study in a tertiary Irish maternity hospital.

BACKGROUND: Preterm deliveries account for 10% of all births, and are the most important cause of neonatal mortality globally. Despite their frequency, there is a paucity of information known about usual patterns of preterm labor, as previous studies which critically defined the normal progression of labor excluded preterm gestations. OBJECTIVE: To compare the durations of the first, second and third stages of spontaneous preterm labor in nulliparous and multiparous women at varying preterm gestations. METHODS: A retrospective observational study was undertaken of women admitted in spontaneous preterm labor from January 2017 to December 2020 with viable singleton gestations between 24 and 36 + 6 weeks' gestation who then proceeded to have a vaginal delivery. There were 512 cases following exclusion of preterm inductions of labor, instrumental vaginal deliveries, provider-initiated pre-labor Caesarean sections and emergency intrapartum Caesarean sections. The data was then examined to determine our outcomes of interest including the durations of the first, second and third stages of preterm labor, analyzing results by parity and gestation. For comparison, we reviewed data of term spontaneous labors and spontaneous vaginal deliveries during the same study period, identifying 8339 cases. FINDINGS: 97.6% of participants achieved a spontaneous cephalic vaginal delivery with the remainder undergoing an assisted breech birth. 5.7% of gestations delivered spontaneously between 24 + 0 and 27 + 6 weeks, with most births at gestations greater than 34 weeks (74%). The second stage duration (mean 15 vs 32 vs 32 mins respectively) was significantly different across the three gestation periods (p < 0.05), but was notably much quicker in extremely preterm labors. The first and third stage durations were similar between all gestational age groups with no statistically significant differences in results. There was a significant influence of parity on the first and second stages of labor, with multiparous women progressing more quickly than nulliparae (p < 0.001). CONCLUSION: The duration of spontaneous preterm labor is described. Multiparous women progress more quickly in the first and second stages of preterm labor than nulliparous women.

Demographic changes in primiparae of Irish ethnicity between 2000 and 2020.

BACKGROUND: Trends in maternal demographic changes linked to lifestyle and socio-economic conditions reflect greatly on maternal, perinatal and infant mortality rates. Hospital data reflect a heterogenous population where specific demographic changes may not be obvious. OBJECTIVES: To report yearly demographic changes in Irish primiparae from 2000 to 2020, specifically looking at age, BMI, smoking and marital status of patients attending the Coombe Women and Infant's University Hospital (CWIUH). METHODS: Retrospective report of demographic details contemporaneously documented on the CWIUH data base. FINDINGS: In the years 2000 to 2020 inclusive there were 47,659 primiparous women of Irish ethnicity delivered at the CWIUH (70.2% of the total primiparae), of those 99.3% were Caucasian. There was a significant rise in mean age at first delivery in Irish mothers; 26.0 years old in the 2000 to 30.9 years old in 2020 associated with a rise in mean BMI of 9.1%. Smoking rates (ever smoked) showed a significant reduction from 53.9% in 2000 to 39.3% in 2020. There was a significant decrease in rates of marriage, with 61.9% married in 2000 compared to 46.3% in 2020. Birth weight and prematurity rates remained unchanged, with fall in mean gestational age at first delivery from 279.3 days in 2000 to 275.8 days in 2020. CONCLUSION: This study highlights that Irish primiparae are older, heavier, less likely to smoke and to be married than they were 20 years ago. These trends are an interesting glimpse into changing economic and cultural climate over just the past 2 decades.

Targeting granulocyte-macrophage colony-stimulating factor in epithelial and vascular remodeling in experimental eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated clinicopathologic disease of the esophagus characterized by an eosinophil-predominant inflammatory infiltrate. A clinical hallmark is extensive tissue remodeling including basal zone hyperplasia, fibrosis, and angiogenesis. However, the cellular mechanisms responsible for these processes are not fully defined. We hypothesized that targeting granulocyte-macrophage colony-stimulating factor (GM-CSF; an agonist cytokine linked with eosinophil survival and activation) would be protective in a preclinical model of EoE. METHODS: Eosinophilic esophagitis-like esophageal inflammation was induced in the L2-IL5OXA EoE mouse model, and GM-CSF production was assessed by mRNA and protein analyses. Granulocyte-macrophage colony-stimulating factor-receptor-alpha expression patterns were examined by flow cytometric and immunofluorescence analysis. L2-IL5OXA EoE mice were treated with anti-GM-CSF neutralizing antibody or isotype control and assessed for histopathological indices of eosinophilia, epithelial hyperplasia, and angiogenesis by immunohistochemistry and RT-PCR. RESULTS: Significantly increased levels of esophageal GM-CSF expression was detected in the L2-IL5OXA mouse EoE model during active inflammation. Granulocyte-macrophage colony-stimulating factor-receptor-alpha was predominantly expressed on esophageal eosinophils during EoE, in addition to select cells within the lamina propria. Anti-GM-CSF neutralization in L2-IL5OXA EoE mice resulted in a significant diminution of epithelial eosinophilia in addition to basal cell hyperplasia and vascular remodeling. This treatment response was independent of effects on esophageal eosinophil maturation or activation. CONCLUSION: Granulocyte-macrophage colony-stimulating factor is a potential therapeutic target to reduce esophageal eosinophilia and remodeling.

Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis.

Central to inflammatory bowel disease (IBD) pathogenesis is loss of mucosal barrier function. Emerging evidence implicates extracellular adenosine signaling in attenuating mucosal inflammation. We hypothesized that adenosine-mediated protection from intestinal barrier dysfunction involves tissue-specific signaling through the A2B adenosine receptor (Adora2b) at the intestinal mucosal surface. To address this hypothesis, we combined pharmacologic studies and studies in mice with global or tissue-specific deletion of the Adora2b receptor. Adora2b(-/-) mice experienced a significantly heightened severity of colitis, associated with a more acute onset of disease and loss of intestinal epithelial barrier function. Comparison of mice with Adora2b deletion on vascular endothelial cells (Adora2b(fl/fl)VeCadCre(+)) or intestinal epithelia (Adora2b(fl/fl)VillinCre(+)) revealed a selective role for epithelial Adora2b signaling in attenuating colonic inflammation. In vitro studies with Adora2b knockdown in intestinal epithelial cultures or pharmacologic studies highlighted Adora2b-driven phosphorylation of vasodilator-stimulated phosphoprotein (VASP) as a specific barrier repair response. Similarly, in vivo studies in genetic mouse models or treatment studies with an Adora2b agonist (BAY 60-6583) recapitulate these findings. Taken together, our results suggest that intestinal epithelial Adora2b signaling provides protection during intestinal inflammation via enhancing mucosal barrier responses.

Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis.

Pharmacological stabilization of hypoxia-inducible factor (HIF) through prolyl hydroxylase (PHD) inhibition limits mucosal damage associated with models of murine colitis. However, little is known about how PHD inhibitors (PHDi) influence systemic immune function during mucosal inflammation or the relative importance of immunological changes to mucosal protection. We hypothesized that PHDi enhances systemic innate immune responses to colitis-associated bacteremia. Mice with colitis induced by trinitrobenzene sulfonic acid were treated with AKB-4924, a new HIF-1 isoform-predominant PHDi, and clinical, immunological, and biochemical endpoints were assessed. Administration of AKB-4924 led to significantly reduced weight loss and disease activity compared with vehicle controls. Treated groups were pyrexic but did not become subsequently hypothermic. PHDi treatment augmented epithelial barrier function and led to an approximately 50-fold reduction in serum endotoxin during colitis. AKB-4924 also decreased cytokines involved in pyrogenesis and hypothermia, significantly reducing serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α while increasing IL-10. Treatment offered no protection against colitis in epithelial-specific HIF-1α-deficient mice, strongly implicating epithelial HIF-1α as the tissue target for AKB-4924-mediated protection. Taken together, these results indicate that inhibition of prolyl hydroxylase with AKB-4924 enhances innate immunity and identifies that the epithelium is a central site of inflammatory protection afforded by PHDi in murine colitis.

Detrimental role of the airway mucin Muc5ac during ventilator-induced lung injury.

Acute lung injury (ALI) is associated with high morbidity and mortality in critically ill patients. At present, the functional contribution of airway mucins to ALI is unknown. We hypothesized that excessive mucus production could be detrimental during lung injury. Initial transcriptional profiling of airway mucins revealed a selective and robust induction of MUC5AC upon cyclic mechanical stretch exposure of pulmonary epithelia (Calu-3). Additional studies confirmed time- and stretch-dose-dependent induction of MUC5AC transcript or protein during cyclic mechanical stretch exposure in vitro or during ventilator-induced lung injury in vivo. Patients suffering from ALI showed a 58-fold increase in MUC5AC protein in their bronchoalveolar lavage. Studies of the MUC5AC promoter implicated nuclear factor κB in Muc5ac induction during ALI. Moreover, mice with gene-targeted deletion of Muc5ac⁻/⁻ experience attenuated lung inflammation and pulmonary edema during injurious ventilation. We observed that neutrophil trafficking into the lungs of Muc5ac⁻/⁻ mice was selectively attenuated. This implicates that endogenous Muc5ac production enhances pulmonary neutrophil trafficking during lung injury. Together, these studies reveal a detrimental role for endogenous Muc5ac production during ALI and suggest pharmacological strategies to dampen mucin production in the treatment of lung injury.

Low birthweight and preterm birth rates 1 year before and after the Irish workplace smoking ban.

OBJECTIVE: It is well-established that maternal smoking has adverse birth outcomes (low birthweight, LBW, and preterm births). The comprehensive Irish workplace smoking ban was successfully introduced in March 2004. We examined LBW and preterm birth rates 1 year before and after the workplace smoking ban in Dublin. DESIGN: A cross-sectional observational study analysing routinely collected data using the Euroking K2 maternity system. SETTING: Coombe University Maternal Hospital. POPULATION: Only singleton live births were included for analyses (7593 and 7648, in 2003 and 2005, respectively). METHODS: Detailed gestational and clinical characteristics were collected and analysed using multivariable logistic regression analyses and subgroup analyses. MAIN OUTCOME MEASURES: Maternal smoking rates, mean birthweights, and adjusted odds ratios (ORs) of LBW and preterm births in 2005 versus 2003. RESULTS: There was a 25% decreased risk of preterm births (OR, 0.75; 95% CI, 0.59-0.96), a 43% increased risk of LBW (OR, 1.43; 95% CI, 1.10-1.85), and a 12% fall in maternal smoking rates (from 23.4 to 20.6%) in 2005 relative to 2003. Such patterns were significantly maintained when specific subgroups were also analysed. Mean birthweights decreased in 2005, but were not significant (P=0.99). There was a marginal increase in smoking cessation before pregnancy in 2005 (P=0.047). CONCLUSIONS: Significant declines in preterm births and in maternal smoking rates after the smoking ban are welcome signs. However, the increased LBW birth risks might reflect a secular trend, as observed in many industrialised nations, and merits further investigations.

A dominant-negative herpesvirus protein inhibits intranuclear targeting of viral proteins: effects on DNA replication and late gene expression.

The d105 dominant-negative mutant form of the herpes simplex virus 1 (HSV-1) single-stranded DNA-binding protein, ICP8 (d105 ICP8), inhibits wild-type viral replication, and it blocks both viral DNA replication and late gene transcription, although to different degrees (M. Gao and D. M. Knipe, J. Virol. 65:2666-2675, 1991; Y. M. Chen and D. M. Knipe, Virology 221:281-290, 1996). We demonstrate here that this protein is also capable of preventing the formation of intranuclear prereplicative sites and replication compartments during HSV infection. We defined three patterns of ICP8 localization using indirect immunofluorescence staining of HSV-1-infected cells: large replication compartments, small compartments, and no specific intranuclear localization of ICP8. Cells that form large replication compartments replicate viral DNA and express late genes. Cells that form small replication compartments replicate viral DNA but do not express late genes, while cells without viral replication compartments are incapable of both DNA replication and late gene expression. The d105 ICP8 protein blocks formation of prereplicative sites and large replication compartments in 80% of infected cells and formation of large replication compartments in the remaining 20% of infected cells. The phenotype of d105 suggests a correlation between formation of large replication compartments and late gene expression and a role for intranuclear rearrangement of viral DNA and bound proteins in activation of late gene transcription. Thus, these results provide evidence for specialized machinery for late gene expression within replication compartments.