Midwives' personal and professional attitudes towards women's delivery choices, interventions and neonatal care.

OBJECTIVES: Caesarean section (CS) rates in middle- and high-income countries are rising partly due to maternal request. This study aimed to explore the personal and professional attitudes of midwives and nurses towards women's delivery choices, interventions and neonatal care. METHODS: Midwifery and nursing staff at the Coombe hospital were asked to complete a questionnaire concerning decisions for elective CS and neonatal care. The midwives' responses were divided into multiparous and nulliparous according to their own parity. RESULTS: Multiparae and nulliparae did not differ on their personal preferences for their own baby. Only 3% wanted an elective CS in a normal, healthy pregnancy but this increased to 80.2% when there was a breech presentation and 42% if the estimated fetal weight was >4.5 kg. These numbers and trends were very close to the midwives' professional recommendations under the same circumstances. The lower threshold for full resuscitation and ICU care was at 23 and 24 weeks gestation for both personal and professional recommendations. In the case of severely premature babies or babies with a poor prognosis, 54% stated that the approach to neonatal care was correct. CONCLUSIONS: Overall, midwives' professional views reflected what they would want for themselves and their babies. Only 3% recommended an elective CS in a normal, healthy pregnancy making it unlikely that midwives' attitudes are driving the rise in CS rates in Ireland.

Hyperbaric effects on cold stored whole blood following a military dive mission profile.

BACKGROUND: Whole blood (WB) is carried by special operations forces as part of a remote damage control resuscitation strategy. The effects of an underwater mission on the quality and coagulation profile of WB were simulated by exposure to hyperbaric pressures in a chamber. METHODS: WB units collected in CPDA-1 were exposed to three different combinations of hyperbaric pressure and duration of exposure: Group A 153.52 kPa (15.24 msw; 1.52 atm) for 4 h; n = 9, Group B 506.63 kPa (50.29 msw; 5.00 atm) for 1 h; n = 9, Group C 153.52 kPa (15.24 msw; 1.52 atm) for 1 h; n = 7. The following parameters were measured on each unit: prothrombin time/international normalized ratio, activated partial thromboplastin time, thromboelastography and concentration determinations of platelets, lactate, fibrinogen, and lactate dehydrogenase. Each sample underwent baseline, prepressurization, immediate postpressurization, and 6 h postpressurization laboratory testing. RESULTS: Six hours following hyperbaric exposure, the lactate concentration in group C was higher than prepressurization measurement and the platelet concentration in Group A was lower than prepressurization measurement. There were no changes in any of the other analyzed biochemical, coagulation and thromboelastogram parameters following exposure to hyperbaric stress. DISCUSSION: These data suggest that pressurization of WB up to 5 atm did not impact parameters tested. Changes observed in lactate and platelet count need further study, as well as complementary testing of red blood cell integrity. Further investigation of the hyperbaric extremes is necessary to determine if there is a damage inducing pressure to which WB should not be exposed.

sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance.

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in ß-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.

Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1.

BACKGROUND: An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association. OBJECTIVE: Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans. METHODS: Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system. RESULTS: Hereditary α-tryptasemia (HαT)-a genetic trait caused by increased α-tryptase-encoding Tryptase-α/ß1 (TPSAB1) copy number resulting in elevated BST level-was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). HαT was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant HαT was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not α- or ß-tryptase homotetramers. CONCLUSIONS: Risk for severe anaphylaxis in humans is associated with inherited differences in α-tryptase-encoding copies at TPSAB1.

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.

Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production.

Persistent dysregulation of IL-6 production and signaling have been implicated in the pathology of various cancers. In systemic mastocytosis, increased serum levels of IL-6 associate with disease severity and progression, although the mechanisms involved are not well understood. Since systemic mastocytosis often associates with the presence in hematopoietic cells of a somatic gain-of-function variant in KIT, D816V-KIT, we examined its potential role in IL-6 upregulation. Bone marrow mononuclear cultures from patients with greater D816V allelic burden released increased amounts of IL-6 which correlated with the percentage of mast cells in the cultures. Intracellular IL-6 staining by flow cytometry and immunofluorescence was primarily associated with mast cells and suggested a higher percentage of IL-6 positive mast cells in patients with higher D816V allelic burden. Furthermore, mast cell lines expressing D816V-KIT, but not those expressing normal KIT or other KIT variants, produced constitutively high IL-6 amounts at the message and protein levels. We further demonstrate that aberrant KIT activity and signaling are critical for the induction of IL-6 and involve STAT5 and PI3K pathways but not STAT3 or STAT4. Activation of STAT5A and STAT5B downstream of D816V-KIT was mediated by JAK2 but also by MEK/ERK1/2, which not only promoted STAT5 phosphorylation but also its long-term transcription. Our study thus supports a role for mast cells and D816V-KIT activity in IL-6 dysregulation in mastocytosis and provides insights into the intracellular mechanisms. The findings contribute to a better understanding of the physiopathology of mastocytosis and suggest the importance of therapeutic targeting of these pathways.

Caesarean section rates in women in the Republic of Ireland who chose to attend their obstetrician privately: a retrospective observational study.

BACKGROUND: Caesarean section (CS) rates are increasing and there are wide variations in rates internationally and nationally. There is evidence that women who attend their obstetrician privately have a higher incidence of CS than those who attend publicly. The purpose of this observational study was to further investigate why CS rates may be higher in women who chose to attend their obstetrician privately. METHODS: This study analysed data collected as part of the clinical records by midwives at the woman's first antenatal appointment in a large European maternity hospital. All women who delivered between the years 2009 and 2017 were included. Data were analysed both cross-sectionally and longitudinally. RESULTS: Overall, 73,266 women had a singleton pregnancy and 1830 had a multiple pregnancy. Of the packages of maternity care, 75.2% chose public, 10.8% chose semiprivate and 14.0% chose private. During the study, 11,991 women attended the hospital for their first and second pregnancies. Overall, women who attended privately were older and had higher proportions of infertility treatment and history of miscarriage (all p < 0.001) compared to those publicly-funded. Private patients were more likely to have a history of infertility, a history of miscarriage, a multiple pregnancy and to be ≥35 yrs. They had lower rates of obesity, smoking and illicit drug use in pregnancy (all p < 0.001). In women who chose private care, the overall rate of CS was higher compared to women choosing publicly-funded (42.7% vs 25.3%, p < 0.001) The increase was due to an increase in elective rather than emergency CS. The increase in elective CS fell after adjustment for clinical risks. In the longitudinal analysis, 89.7% chose the same package second time around. Women who changed from public to private care for the second pregnancy were more likely to have had a previous emergency CS or admission to the Neonatal Unit. CONCLUSIONS: This study suggests that the increased CS rate in women privately insured may be attributed, in part, to the fact that women who can afford health insurance choose continuity of care from a senior obstetrician because they are risk adverse and wish to have the option of an elective CS.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.

Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis.

BACKGROUND: During IgE-mediated immediate hypersensitivity reactions, vascular endothelial cells permeabilize in response to mast cell mediators. We have demonstrated previously that patients and mice with signal transducer and activator of transcription 3 (STAT3) mutations (autosomal dominant hyper-IgE syndrome [AD-HIES]) are partially protected from anaphylaxis. OBJECTIVES: We sought to study the mechanism by which STAT3 contributes to anaphylaxis and determine whether small-molecule inhibition of STAT3 can prevent anaphylaxis. METHODS: Using unaffected and STAT3-inhibited or genetic loss-of-function samples, we performed histamine skin prick tests, investigated the contribution of STAT3 to animal models of anaphylaxis, and measured endothelial cell permeability, gene and protein expression, and histamine receptor-mediated signaling. RESULTS: Although mouse mast cell degranulation was minimally affected by STAT3 blockade, mast cell mediator-induced anaphylaxis was blunted in Stat3 mutant mice with AD-HIES and in wild-type mice subjected to small-molecule STAT3 inhibition. Histamine skin prick test responses were diminished in patients with AD-HIES. Human umbilical vein endothelial cells derived from patients with AD-HIES or treated with a STAT3 inhibitor did not signal properly through Src or cause appropriate dissolution of the adherens junctions made up of the proteins vascular endothelial-cadherin and ß-catenin. Furthermore, we found that diminished STAT3 target microRNA17-92 expression in human umbilical vein endothelial cells from patients with AD-HIES is associated with increased phosphatase and tensin homolog (PTEN) expression, which inhibits Src, and increased E2F transcription factor 1 expression, which regulates ß-catenin cellular dynamics. CONCLUSIONS: These data demonstrate that STAT3-dependent transcriptional activity regulates critical components for the architecture and functional dynamics of endothelial junctions, thus permitting vascular permeability.

Drug use in pregnancy in Ireland's capital city: A decade of trends and outcomes.

OBJECTIVE: The aim of this study was to present contemporary trends in opiate use disorder (OUD) and substance use in pregnancy in Ireland, with associated obstetric outcomes, over the last ten years. STUDY DESIGN: This retrospective observational cohort study was conducted at an Irish tertiary maternity unit. All women with OUD or substance use in pregnancy delivered under this service between 2010 and 2019 were included. Drug-exposure was self-reported. Data was collected by combining electronic and hand-held patient records. Trends and outcomes were analysed by year of delivery. Approval for the study was granted by the institution's clinical governance committee. RESULTS: Of the 82,669 women delivered, 525 had OUD or substance use in pregnancy (1 in every 160 women booking). 11.6% were homeless, 20.0% were in full-time employment and 91.0% smoked tobacco in pregnancy. 66.3% had a history of psychiatric disorders. Over the ten years, there was a significant reduction in women delivered with OUD or substance use in pregnancy (0.8 % to 0.4 %, RR 0.55, 95 % CI 0.36-0.85), significant reduction in the proportion of women on Opioid-Substitute-Treatment (OST, RR 0.66 95 % CI 0.51-0.87) and an increase in mean maternal age (30.7to32.0 years). Rates of cocaine and cannabis consumption increased (20.6 %, RR 3.8, 95 % CI 1.57-9.44: 24.0 %, RR 3.7, 95 % CI 1.58-8.86 respectively). The maternal mortality rate was 380.9:100,000 births. The perinatal mortality rate was 15.6:1000 births. The preterm birth rate was 17.9 %, with a mean birth weight of 2832 g. The rate of NICU admission was 52.0 % and the mean length of stay was 22.4 days. Amongst the smaller OUD population, the rate of NICU admission for Neonatal Abstinence Syndrome (NAS) and treatment for NAS increased over the study timeframe (36.0 %, RR 2.97, 95 % CI 1.86-4.75: 28.5 %, RR 2.92, 95 % CI 1.70-5.0 respectively). CONCLUSIONS: The obstetric population attending an Irish antenatal service with opiate use disorder or substance exposure is reducing in size with older patients, less opioid substitute therapy and increasing cocaine and cannabis use. These women have high rates of maternal and perinatal morbidity and mortality. Specialist antenatal addiction services, coordinated by the drug-liaison midwife, are critical in adapting care to respond to this dynamic and vulnerable patient cohort.

Outcomes of Uterine Rupture in the Setting of the Unscarred Compared With the Scarred Uterus.

Uterine rupture is a rare obstetric complication that is associated with maternal and neonatal morbidity and mortality. The aim of this study was to examine uterine rupture and its outcomes in the setting of the unscarred compared with the scarred uterus. A retrospective observational cohort study was performed examining all cases of uterine rupture in three tertiary care hospitals in Dublin, Ireland, over a 20-year period. The primary outcome was perinatal mortality rate with uterine rupture, which was 11.02% (95% CI 6.5-17.3). There was no significant difference in perinatal mortality between cases of scarred and unscarred uterine rupture. Unscarred uterine rupture was associated with higher maternal morbidity , defined as major obstetric hemorrhage or hysterectomy.

Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.

Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from overexpression of replicated TPSAB1 loci encoding canonical α-tryptase protein owing to coinheritance of a linked overactive promoter element. Modeling BST levels based on TPSAB1 replication number, we generate new individualized clinical reference values for the upper limit of normal. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (eg, >100 ng/mL), which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within normal limits for certain individuals with HαT.

Resolving the genetics of human tryptases: implications for health, disease, and clinical use as a biomarker.

PURPOSE OF REVIEW: To discuss our evolving understanding of the genetic variation in human tryptases and recent advances in associated clinical phenotypes. RECENT FINDINGS: Serum tryptase levels have long been used as biomarkers in clinical practice to diagnose mast cell-associated disorders and mast cell-mediated reactions but the contribution of specific secreted isoforms of human tryptases and their role(s) in health and disease has only recently begun to be illuminated. It is now recognized that hereditary alpha-tryptasemia (HαT) is a common genetic trait and the commonest cause for elevated basal serum tryptase (BST), where it can both contribute to mast cell-associated phenotypes, and potentially confound their correct diagnosis. Expression of different tryptase isoforms is now recognized to be associated with specific clinical phenotypes including clonal and nonclonal mast cell-associated disorders as well as certain asthma endotypes. These disparate impacts on clinical disorders may result from differences in enzymatic activities of mature α-tryptases and ß-tryptases, and the unique substrate profile and stability of heterotetrameric mature α/ß-tryptases recently described to naturally occur. SUMMARY: Variable copy number and isoform expression of tryptases differentially impact diseases and reactions associated with mast cells in humans. Recent advances in understanding of genetics governing BST levels have refined our understanding and the clinical use of this biomarker. In the future, incorporation of tryptase genotyping will likely be integral to the work-up and trial design of patients with phenotypes impacted by mast cells ranging from asthma to mastocytosis.

Activation of Wnt5A signaling is required for CXC chemokine ligand 12-mediated T-cell migration.

Chemokines mediate the signaling and migration of T cells, but little is known about the transcriptional events involved therein. Microarray analysis of CXC chemokine ligand (CXCL) 12-treated T cells revealed that Wnt ligands are significantly up-regulated during CXCL12 treatment. Real-time polymerase chain reaction and Western blot analysis confirmed that the expression of noncanonical Wnt pathway members (eg, Wnt5A) was specifically up-regulated during CXCL12 stimulation, whereas beta-catenin and canonical Wnt family members were selectively down-regulated. Wnt5A augmented signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C. Moreover, Wnt5A expression was required for CXCL12-mediated T-cell migration, and rWnt5A sensitized human T cells to CXCL12-induced migration. Furthermore, Wnt5A expression was also required for the sustained expression of CXCR4. These results were further supported in vivo using EL4 thymoma metastasis as a model of T-cell migration. Together, these data demonstrate that Wnt5A is a critical mediator of CXCL12-CXCR4 signaling and migration in human and murine T cells.

Assessment of antenatal anxiety, depression and obsessive-compulsive disorder in pregnant women in the COVID-19 era.

OBJECTIVE: To assess the mental health of pregnant women, with reference to anxiety, depression and obsessive-compulsive (OC) symptoms, during the COVID-19 pandemic. METHODS: A cross-sectional survey was conducted in Ireland during the third wave of the pandemic between February and March 2021. Psychiatric, social and obstetric information was collected from pregnant women in a Dublin maternity hospital, alongside self-reported measures of mental health status. RESULTS: Of 392 women responding, 23.7% had anxiety, scoring >9 for GAD-7 (7-item generalised anxiety disorder), 20.4% had depression, scoring >9 for PHQ-9 (9-item depression screening tool: Patient health questionnaire) and 10.3% had obsessive-compulsive disorder (OCD), scoring >13 for Yale-Brown obsessive-compulsive scale symptom checklist (Y-BOCS). Amongst self-reported OCD symptoms, there was a preponderance for obsessions rather than compulsions. Of 392 women, 36.2% described their mental health as worse during the pandemic, most frequently describing symptoms of anxiety and sleep disturbance. When analysed against test scores, self-reported worsening of mental health was significantly associated with higher scores on the GAD-7, PHQ-9 and Y-BOCS scales. The three scores were positively interrelated. Poor mental health scores were associated with self-reported strain in relationship with the baby's father, and current or previous history of mental illness. CONCLUSION: This study found high levels of depression, anxiety and OC symptoms amongst pregnant women during COVID-19. This highlights the vulnerability of this group to mental illness and the importance of enhanced screening and support during pandemics.

External cephalic version - A 10-year review of practice.

INTRODUCTION: Following the term breech trial (TBT), the incidence of Caesarean section secondary to breech presentations increased, from 76.9 % to 89.7 %. External Cephalic Version (ECV) is a safe effective method to reduce non-cephalic presentation at time of delivery. METHODS: Retrospective audit of all the ECV procedures performed at a tertiary women's hospital between Jan 2010 and Jan 2020. RESULTS: The success rate of ECV was 54.5 %. The rate of vaginal birth following successful ECV was 73.6 % and rate of Caesarean 26.4 %, compared to 96.4 % for those with unsuccessful ECV (P < 0.0001). Factors found to be associated with increased success rates was the use of Intravenous terbutaline (P = 0.03), fetal birth weight ≥3.5 kg (P = 0.0001) and when the procedure is performed by an experienced operator who performed over 20 ECV procedures (P < 0.0001). CONCLUSION: ECV is a safe and effective procedure to reduce Caesarean section rates secondary to breech presentation. A dedicated ECV clinic with experienced operators and the use of intravenous terbutaline could improve success rate of ECV and reduce the number of Caesareans for breech presentation.

Trends in private maternity care in Ireland's capital during and after the Great Economic Recession 2009-2017.

BACKGROUND: Maternity care in hospitals in the Republic of Ireland is funded by a hybrid of public finance and private health insurance. AIMS: The aim of this longitudinal observational study was to investigate the annual trends in maternity care from 2009 to 2017 during and after the Great Economic Recession. METHODS: All women who delivered a singleton baby weighing ≥ 500 g during the 9 years (2009-2017) were included. Detailed clinical and sociodemographic details were computerised at the first antenatal visit by a trained midwife. Women who delivered their first baby during the study were analysed longitudinally if they delivered again during the 9 years. RESULTS: The mean age of the 73,266 women was 31.3 ± 5.6 years, 40.1% were nulliparas, and 70.3% were Irish-born. Overall, 75.2% opted for the public, 10.8% for the semi-private, and 14.0% for the private package of maternity care. Over the 9 years, the number of women choosing private and semi-private care decreased by 21.6% and 35.3%, respectively, whereas the number of women using public care increased by 12.3%. Most women opted for the same package of care in subsequent pregnancies. CONCLUSIONS: Ireland's recent economic recession was accompanied by an overall decrease in the number of women choosing private maternity care after 2009. Furthermore, economic recovery with increasing female employment after 2012 was not associated with a recovery in demand for private care. These findings have important implications for healthcare policies and for the future organisation and funding of our maternity services.

Heparan sulfate proteoglycan modulation of Wnt5A signal transduction in metastatic melanoma cells.

Heparan sulfate proteoglycans (HSPGs) are important modulators for optimizing signal transduction of many pathways, including the Wnt pathways. We demonstrate that HSPG glycosaminoglycan levels increased with increasing metastatic potential of melanoma cells. Previous studies have demonstrated that Wnt5A increases the invasiveness of melanoma cells. We further demonstrate that HSPGs potentiate Wnt5A signaling, since enzymatic removal of the HSPG backbone resulted in a decrease in cellular Wnt5A levels, an increase in secreted Wnt5A in cell media, a decrease in downstream signaling, and ultimately, a decrease in invasiveness. Specifically, syndecan 1 and syndecan 4 expression correlated to Wnt5A expression and melanoma malignancy. Knockdown of syndecan 1 or 4 caused decreases in cell invasion, which could be restored by treating the cells with recombinant Wnt5A. These data indicate that syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop, the activation of which leads to increased metastasis of melanoma.