Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives.

The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.

Discrimination of pancreato-biliary cancer and pancreatitis patients by non-invasive liquid biopsy.

BACKGROUND: Current diagnostics for the detection of pancreato-biliary cancers (PBCs) need to be optimized. We therefore propose that methylated cell-free DNA (cfDNA) derived from non-invasive liquid biopsies serves as a novel biomarker with the ability to discriminate pancreato-biliary cancers from non-cancer pancreatitis patients. METHODS: Differentially methylated regions (DMRs) from plasma cfDNA between PBCs, pancreatitis and clinical control samples conditions were identified by next-generation sequencing after enrichment using methyl-binding domains and database searches to generate a discriminatory panel for a hybridization and capture assay with subsequent targeted high throughput sequencing. RESULTS: The hybridization and capture panel, covering around 74 kb in total, was applied to sequence a cohort of 25 PBCs, 25 pancreatitis patients, 25 clinical controls, and seven cases of Intraductal Papillary Mucinous Neoplasia (IPMN). An unbiased machine learning approach identified the 50 most discriminatory methylation markers for the discrimination of PBC from pancreatitis and controls resulting in an AUROC of 0.85 and 0.88 for a training (n = 45) and a validation (n = 37) data set, respectively. The panel was also able to distinguish high grade from low grade IPMN samples. CONCLUSIONS: We present a proof of concept for a methylation biomarker panel with better performance and improved discriminatory power than the current clinical marker CA19-9 for the discrimination of pancreato-biliary cancers from non-cancerous pancreatitis patients and clinical controls. This workflow might be used in future diagnostics for the detection of precancerous lesions, e.g. the identification of high grade IPMNs vs. low grade IPMNs.

Trends in Term Intrapartum Stillbirth in Norway.

Importance: Fetal death during labor at term is a complication that is rarely studied in high-income countries. There is a need for large population-based studies to examine the rate of term intrapartum stillbirth in high-income countries and the factors associated with its occurrence. Objective: To evaluate trends in term intrapartum stillbirth over time and to investigate the association between the trends and term intrapartum stillbirth risk factors from 1999 to 2018 in Norway. Design, Setting, and Participants: This cohort study used data from the Medical Birth Registry of Norway from 1999 to 2018 to examine rates of term intrapartum stillbirth and risk factors associated with this event. A population of 1 021 268 term singleton pregnancies without congenital anomalies or antepartum stillbirths was included in analyses, which were performed from September 2022 to February 2023. Exposure: The main exposure variable was time, which was divided into four 5-year periods: 1999 to 2003, 2004 to 2008, 2009 to 2013, and 2014 to 2018. Main Outcomes and Measures: The primary study outcome was term intrapartum stillbirth. Risk ratios were calculated, and multivariable logistic regression analyses were conducted to identify factors associated with secular trends of term intrapartum stillbirth. Results: The study population consisted of 1 021 268 term singleton births (maternal mean [SD] age, 29.72 [5.01] years; mean [SD] gestational age, 39.69 [1.27] weeks). During the study period, there were 95 term intrapartum stillbirths (0.09 per 1000 births). Maternal age, the proportion of individuals born in a country other than Norway, and the prevalence of gestational diabetes, labor induction, operative vaginal delivery, and previous cesarean delivery increased over the course of the study period. Conversely, the prevalence of infants large for gestational age, hypertensive disorder in pregnancy, and spontaneous vaginal delivery and the proportion of individuals who smoked decreased. The term intrapartum stillbirth rate decreased by 87% (95% CI, 68%-95%) from 0.15 per 1000 births in 1999 to 2008 to 0.02 per 1000 births in 2014 to 2018. Three in 4 term intrapartum stillbirths (70 of 95) occurred during intrapartum operative deliveries. The increased prevalence of older maternal age and obstetric risk factors were not associated with the variation in intrapartum stillbirth rates among the time periods. The prevalence of term intrapartum stillbirth was higher for individuals who gave birth in maternity units with fewer than 3000 annual births (adjusted odds ratio, 1.67; 95% CI, 1.07-2.61) than for those who gave birth in units with 3000 or more annual births. Conclusions and Relevance: Findings of this study suggest that, despite increases in maternal and obstetric risk factors, term intrapartum stillbirth rates substantially decreased during the study period. Reasons for this decrease may be due to improvements in intrapartum care.

Neonatal outcomes associated with time from a high fetal blood lactate concentration to operative delivery.

INTRODUCTION: Adjunctive technologies to cardiotocography intend to increase the specificity of the diagnosis of fetal hypoxia. If correctly diagnosed, time to delivery could affect neonatal outcome. In the present study, we aimed to investigate the effect of time from when fetal distress is indicated by a high fetal blood sample (FBS) lactate concentration to operative delivery on the risk of adverse neonatal outcomes. MATERIAL AND METHODS: We conducted a prospective observational study. Deliveries with a singleton fetus in cephalic presentation at 36+0 weeks of gestation or later were included. Adverse neonatal outcomes, related to decision-to-delivery interval (DDI), were investigated in operative deliveries indicated by an FBS lactate concentration of at least 4.8 mmol/L. We applied logistic regression to estimate crude and adjusted odds ratios (aOR) of various adverse neonatal outcomes, with associated 95% confidence intervals (CI), for a DDI exceeding 20 minutes, compared with a DDI of 20 minutes or less. CLINICALTRIALS: gov Identifier: NCT04779294. RESULTS: The main analysis included 228 women with an operative delivery indicated by an FBS lactate concentration of 4.8 mmol/L or greater. The risk of all adverse neonatal outcomes was significantly increased for both DDI groups compared with the reference group (deliveries with an FBS lactate below 4.2 mmol/L within 60 minutes before delivery). In operative deliveries indicated by an FBS lactate concentration of 4.8 mmol/L or more, there was a significantly increased risk of a 5-minute Apgar score less than 7 if the DDI exceeded 20 minutes, compared with a DDI of 20 minutes or less (aOR 8.1, 95% CI 1.1-60.9). We found no statistically significant effect on other short-term outcomes for deliveries with DDI longer than 20 minutes, compared with those with DDI of 20 minutes or less (pH ≤7.10: aOR 2.0, 95% CI 0.5-8.4; transfer to the neonatal intensive care unit: aOR 1.1, 95% CI 0.4-3.5). CONCLUSIONS: After a high FBS lactate measurement, the increased risk of adverse neonatal outcome is further augmented if the DDI exceeds 20 minutes. These findings give support to current Norwegian guidelines for intervention in cases of fetal distress.

Transverse Incision for Pancreatoduodenectomy Reduces Wound Complications: A Single-Center Analysis of 399 Patients.

BACKGROUND: Even if the minimally invasive approach is advancing in pancreatic surgery, the open approach is still the standard for a pancreatoduodenectomy. There are two types of incisions used: the midline incision (MI) and transverse incision (TI). The aim of this study was to compare these two incision types, especially regarding wound complications. METHODS: A retrospective review of 399 patients who underwent a pancreatoduodenectomy at the University Hospital Erlangen between 2012 and 2021 was performed. A total of 169 patients with MIs were compared with 230 patients with TIs, with a focus on postoperative fascial dehiscence, postoperative superficial surgical site infection (SSSI) and the occurrence of incisional hernias during follow-up. RESULTS: Postoperative fascial dehiscence, postoperative SSSI and incisional hernias occurred in 3%, 8% and 5% of patients, respectively. Postoperative SSSI and incisional hernias were significantly less frequent in the TI group (SSI: 5% vs. 12%, p = 0.024; incisional hernia: 2% vs. 8%, p = 0.041). A multivariate analysis confirmed the TI type as an independent protective factor for the occurrence of SSSI and incisional hernias (HR 0.45 (95% CI = 0.20-0.99), p = 0.046 and HR 0.18 (95% CI = 0.04-0.92), p = 0.039, respectively). CONCLUSION: Our data suggest that the transverse incision for pancreatoduodenectomy is associated with reduced wound complications. This finding should be confirmed by a randomized controlled trial.

Interleukin-3 protects against viral pneumonia in sepsis by enhancing plasmacytoid dendritic cell recruitment into the lungs and T cell priming.

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive. Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis. Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections). Measurements and main results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3-deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections. Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs.

Onset of labor and use of analgesia in women using thromboprophylaxis with 2 doses of low-molecular-weight heparin: insights from the Highlow study.

BACKGROUND: Peripartum management of women using low-molecular-weight heparin (LMWH) varies widely. Minimum time intervals are required between LMWH injection and neuraxial procedure, and they differ by dose. OBJECTIVES: The objective of this study was to describe the onset of labor and use of analgesia in women using LMWH and to compare practices between intermediate-dose and low-dose LMWH. METHODS: In the Highlow study (NCT01828697), 1110 women were randomized to intermediate-dose or low-dose LMWH and were instructed to discontinue LMWH when labor commenced unplanned or 24 hours prior to planned delivery. The required time interval since last injection to receive a neuraxial procedure was ≥24 hours for intermediate-dose LMWH or ≥12 hours for low-dose LMWH. RESULTS: In total, 1018 women had an ongoing pregnancy for ≥24 weeks. Onset of labor was spontaneous in 198 of 509 (39%) women on intermediate-dose LMWH and in 246 of 509 (49%) on low-dose LMWH. With unplanned onset, a neuraxial procedure was performed in 37% on intermediate-dose and in 48% on low-dose LMWH (risk difference -11%, 95% CI -20% to -2%). Based on time interval, 61% on intermediate-dose and 82% on low-dose LMWH were eligible for a neuraxial procedure. With planned onset, 68% on intermediate-dose and 66% on low-dose LMWH received a neuraxial procedure, whereas 81% and 93%, respectively, were eligible for a neuraxial procedure (risk difference -13%, 95% CI -18% to -8%). CONCLUSION: With spontaneous onset of labor, neuraxial procedures were performed less often in women using intermediate-dose LMWH. Irrespective of onset, fewer women on intermediate-dose LMWH than those on low-dose LMWH were eligible for neuraxial procedures based on required time intervals since the last LMWH injection.

A Quantitative LC-MS/MS Method for Distinguishing the Tau Protein Forms Phosphorylated and Nonphosphorylated at Serine-396.

Hyperphosphorylated tau protein is well-known to be involved in the formation of neurofibrillary tangles and the progression of age-related neurodegenerative diseases (tauopathies), including Alzheimer's Disease (AD). Tau protein phosphorylated at serine-396 (pS396-tau) is often linked to disease progression, and we therefore developed an analytical method to measure pS396-tau in cerebrospinal fluid (CSF) in humans and animal models of AD. In the S396-region, multiple phosphorylation sites are present, causing structural complexity and sensitivity challenges for conventional bottom-up mass spectrometry approaches. Here, we present an indirect LC-MS/MS method for quantification of pS396-tau. We take advantage of the reproducible miscleavage caused by S396 being preceded by a lysine (K395) and the proteolytic enzyme trypsin not cleaving when the following amino acid is phosphorylated. Therefore, treatment with trypsin discriminates between the forms of tau with and without phosphorylation at S396 and pS396-tau can be quantified as the difference between total S396-tau and nonphosphorylated S396-tau. To qualify the method, it was successfully applied for quantification of pS396-tau in human CSF from healthy controls and patients with Mild Cognitive Impairment and AD. In addition, the method was applied for rTg4510 mice where a clear dose dependent decrease in pS396-tau was observed in CSF following intravenous administration of a monoclonal antibody (Lu AF87908, hC10.2) targeting the tau epitope containing pS396. Finally, a formal validation of the method was conducted. In conclusion, this sensitive LC-MS/MS-based method for measurement of pS396-tau in CSF allows for quantitative translational biomarker applications for tauopathies including investigations of potential drug induced effects.

Intrapartum pudendal nerve block analgesia and childbirth experience in primiparous women with vaginal birth: A cohort study.

BACKGROUND: A negative childbirth experience has short- and long-term consequences for both mother and child. This study aimed to investigate the association between intrapartum pudendal nerve block (PNB) analgesia and childbirth experience. METHODS: Primiparous women with a singleton cephalic vaginal live births at term at Oslo University Hospital from January 1, 2017, to June 1, 2019, were eligible for inclusion. The main outcome was total score on a childbirth experience questionnaire (range 1.0-4.0, higher score indicates better childbirth experience). An absolute risk difference of 0.10 was considered clinically relevant. Propensity score matching was used to adjust for differences in baseline characteristics between women with and without PNB. The analyses were stratified by spontaneous vs instrumental birth. Subanalyses of the questionnaire's domains (own capacity, professional support, perceived safety, and participation) were performed. RESULTS: Of 979 participating women, mean age was 32 years. Childbirth experience did not differ between women with and without PNB, either in spontaneous (absolute risk difference of the mean: -0.05, P value 0.36) or in instrumental birth (absolute risk difference of the mean: 0.03, P value 0.61). There were no statistically significant differences between PNB group scores for the separate domains. CONCLUSIONS: Women's childbirth experiences did not differ between birthing people with or without PNB, either in spontaneous or in instrumental births. The clinical implications of our study should be interpreted in light of the pain-relieving effects of PNB.PNB should be provided on clinical indication, including for individuals with severe labor pain.

Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. METHODS: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. FINDINGS: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). INTERPRETATION: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. FUNDING: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.

Time to Surgery Does Not Affect Overall or Disease-Free Survival of Patients with Primary Resectable PDAC.

(1) Background: Delay in therapy for pancreatic ductal adenocarcinoma (PDAC) may contribute to a worse outcome. The aim of this study was to investigate the prognostic value of time from diagnosis to surgery in patients undergoing upfront surgery for primarily resectable pancreatic carcinoma. (2) Methods: This retrospective single-center study included 214 patients who underwent primary resection of PDAC from January 2000 to December 2018 at University Hospital Erlangen. Using a minimum p-value approach, patients were stratified according to time to surgery (TtS) into two groups: TtS ≤ 23 days and TtS > 23 days. Postoperative outcome and long-term survival were compared. (3) Results: Median TtS was 25 days. The best cut-off for TtS was determined as 23 days. There were no differences regarding postoperative outcome or overall survival (OS) and disease-free survival (DFS) (OS: 23.8 vs. 20.4 months, p = 0.210, respectively, and DFS: 15.8 vs. 13.6 months, p = 0.187). Multivariate analysis revealed age, lymph node metastasis, tumor differentiation and resection status as significant independent prognostic predictors for OS and DFS. (4) Conclusions: A delay of surgery > 23 days after first diagnosis does not affect overall or disease-free survival of patients with primary resectable PDAC. However, the psychological impact of a delay to patients waiting for surgery should not be underestimated.

Inhibition of P2X7 receptors by Lu AF27139 diminishes colonic hypersensitivity and CNS prostanoid levels in a rat model of visceral pain.

Visceral pain is a prominent feature of various gastrointestinal diseases. The P2X7 receptor is expressed by multiple cell types including dorsal root ganglion satellite glial cells, macrophages, and spinal microglia, all of which have been implicated in nociceptive sensitization. We have used the selective and CNS penetrant P2X7 receptor antagonist Lu AF27139 to explore this receptor's role in distinct rat models of inflammatory and visceral hypersensitivity. Rats injected with CFA in the hindpaw displayed a marked reduction in hindpaw mechanical threshold, which was dose-dependently reversed by Lu AF27139 (3-30 mg/kg, p.o.). In rats injected with TNBS in the proximal colon, the colorectal distension threshold measured distally was significantly lower than sham treated rats at 7 days post-injection (P < 0.001), indicative of a marked central sensitization. Colonic hypersensitivity was also reversed by Lu AF27139 (10-100 mg/kg) and by the κ-opioid receptor agonist U-50,488H (3 mg/kg, s.c.). Moreover, both Lu AF27139 and U-50,488H prevented a TNBS-induced increase in spinal and brain levels of PGE2 and LTB4, as well as an increase in brain levels of PGF2α and TXB2. Lu AF27139 was well tolerated as revealed by a lack of significant effect on rotarod motor function and coordination at all doses tested up to 300 mg/kg. Thus, P2X7 receptor antagonism is efficacious in a rat model of visceral pain, via a mechanism which potentially involves attenuation of microglial function within spinal and/or supraspinal pain circuits, albeit a peripheral site of action cannot be excluded.

Pleural Resident Macrophages and Pleural IRA B Cells Promote Efficient Immunity Against Pneumonia by Inducing Early Pleural Space Inflammation.

Airway infection is a major cause of mortality worldwide. The identification of new mechanisms aiding in effective host immune response is therefore required. Here, we show that the specific depletion of the pleural immune cell compartment during bacterial pneumonia resulted in a reduced pulmonary immune response and increased mortality in mice. Bacterial airway infection provoked early pleural space (PS) inflammation characterized by innate response activator (IRA) B cell development and pleural large resident macrophage (LRM) necroptosis, the repopulation of LRMs being driven by cellular proliferation in situ. Necroptotic LRMs amplified PS inflammation by stimulating pleural Mincle-expressing macrophages whereas IRA B cells contributed partially to GM-CSF-induced PS inflammation. Upon pulmonary infection, the induction of PS inflammation resulted in reduced bacterial burden whereas the specific depletion of pleural resident macrophages led to increased mortality and bacterial burden and reduced pulmonary immunity. Moreover, mice in which B cells were unable to produce GM-CSF exhibited reduced CD103+ dendritic cells and reduced CD4+ T cell numbers in the draining lymph node. Altogether, our results describe a previously unrecognized mechanism of pleural space inflammation necessary for effective protection against bacterial airway infection.

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer.

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5'-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73+ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73+ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73+ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73+ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.

Group B Streptococcus colonization at delivery is associated with maternal peripartum infection.

BACKGROUND: Group B Streptococcus (GBS) is a major cause of serious neonatal infection but its role in maternal morbidity has received little investigation. The aim of this study was to determine whether GBS colonization at delivery is associated with increased risk of maternal peripartum infection. METHODS: In this prospective cohort study, 1746 unselected women had a vaginal-rectal culture taken at the onset of labor. Diagnosis of maternal peripartum infection was based on a combination of two or more signs or symptoms including fever, breast pain, severe wound or pelvic pain, purulent discharge and abnormal laboratory tests including C-reactive protein and white blood cell count occurring from labor until 2 weeks postpartum. The main outcome measure was the proportion of women with maternal peripartum infection according to GBS colonization status. RESULTS: A total of 25.9% (452/1746) women were colonized with GBS. The rate of peripartum infection was almost twice as high in colonized women (49/452 [10.8%]) vs. non-colonized women (81/1294 [6.3%]); OR 1.82 [1.26-2.64], p = 0.002). This association was confirmed in a multivariable model (OR 1.99 [1.35-2.95], p = 0.001). Women diagnosed with peripartum infection had a significantly longer hospital stay compared to women without peripartum infection (4 days (median) vs. 3 days, p < 0.001). Length of hospital stay did not differ between colonized and non-colonized women. Serotype IV GBS was more frequent in colonized women with peripartum infection than in women without peripartum infection (29.3% vs. 12.5%, p = 0.003). CONCLUSIONS: GBS colonization at delivery is associated with increased risk of peripartum infection. Whether this increase is due directly to invasion by GBS or whether GBS colonization is associated with a more general vulnerability to infection remains to be determined.

Knowledge of gestational diabetes mellitus at first consultation in a multi-ethnic pregnant population in the Oslo region, Norway - a cross-sectional study.

Objectives: Gestational diabetes mellitus (GDM) is an increasing problem among pregnant women globally and is associated with short- and long-term consequences for both mother and newborn. The aim of this study was to investigate knowledge of GDM among a multi-ethnic pregnant population at first consultation for GDM in the Oslo region in Norway.Design: We conducted a cross-sectional study using baseline data from a randomised controlled study performed at five diabetic outpatient clinics (DOC) in the Oslo region. Pregnant women diagnosed with GDM following an Oral Glucose Tolerance test (OGTT) with a 2-hours blood glucose level of ≥ 9 mmol/l were included. Women filled out a questionnaire on an electronic tablet at the study entry, and additional data were collected through a recruiting form. Descriptive statistics were performed and associations were investigated using Chi-square test and multiple logistic regression analysis.Results: Of 238 women included in the study, 108 (45.4%) were native Norwegian speakers and 130 (54.6%) were non-native Norwegian speakers. 39.5% of the non-native Norwegian speakers were Asian, 22.5% were African, and 15.5% were from Eastern European Countries. Non-native Norwegian speakers were significantly more likely to have poor knowledge of GDM compared to native Norwegian speakers, adjusted OR = 4.5, 95% CI 1.61-12.5. Sensitivity analyses showed this was not due to poor language skills.Conclusions: Ethnic background was associated with the level of knowledge of GDM. Health professionals should be aware of the various knowledge levels concerning GDM and tailor their information towards women's knowledge. Linguistically- and culturally adapted information regarding GDM may improve knowledge gaps among women with immigrant backgrounds.

Prospective assessment of vacuum deliveries from midpelvic station in a tertiary care university hospital: Frequency, failure rates, labor characteristics and maternal and neonatal complications.

BACKGROUND: Midpelvic vacuum extractions are controversial due to reports of increased risk of maternal and perinatal morbidity and high failure rates. Prospective studies of attempted midpelvic vacuum outcomes are scarce. Our main aims were to assess frequency, failure rates, labor characteristics, maternal and neonatal complications of attempted midpelvic vacuum deliveries, and to compare labor characteristics and complications between successful and failed midpelvic vacuum deliveries. STUDY DESIGN: Clinical data were obtained prospectively from all attempted vacuum deliveries (n = 891) over a one-year period with a total of 6903 births (overall cesarean section rate 18.2% (n = 1258). Student's t-test, Mann-Whitney U-test or Chi-square test for group differences were used as appropriate. Odds ratios and 95% confidence intervals are given as indicated. The uni- and multivariable analysis were conducted both as a complete case analysis and with a multiple imputation approach. A p-value of <0.05 was considered statistically significant. RESULTS: Attempted vacuum extractions from midpelvic station constituted 36.7% (n = 319) of all attempted vacuum extractions (12.9% (n = 891) of all births). Of these 319 midpelvic vacuum extractions, 11.3% (n = 36) failed and final delivery mode was cesarean section in 86.1% (n = 31) and forceps in the remaining 13.9% (n = 5). Successful completion of midpelvic vacuum by 3 pulls or fewer was achieved in 67.1%. There were 3.9% third-degree and no fourth-degree perineal tears. Cup detachments were associated with a significantly increased failure rate (adjusted OR 6.13, 95% CI 2.41-15.56, p< 0.001). CONCLUSION: In our study, attempted midpelvic vacuum deliveries had relatively low failure rate, the majority was successfully completed within three pulls and they proved safe to perform as reflected by a low rate of third-degree perineal tears. We provide data for nuanced counseling of women on vacuum extraction as a second stage delivery option in comparable obstetric management settings with relatively high vacuum delivery rates and low cesarean section rates.

Screening novel CNS drug candidates for P-glycoprotein interactions using the cell line iP-gp: In vitro efflux ratios from iP-gp and MDCK-MDR1 monolayers compared to brain distribution data from mice.

Drug efflux by P-glycoprotein (P-gp, ABCB1) is considered as a major obstacle for brain drug delivery for small molecules. P-gp-expressing cell monolayers are used for screening of new drug candidates during early states of drug development. It is, however, uncertain how well the in vitro studies can predict the in vivo P-gp mediated efflux at the blood-brain barrier (BBB). We previously developed a novel cell line of porcine origin, the iP-gp cell line, with high transepithelial resistance and functional expression of human P-gp. The aim of the present study was to evaluate the applicability of the cell line for screening of P-gp interactions of novel drug candidates. For this purpose, bidirectional fluxes of 14 drug candidates were measured in iP-gp cells and in MDCK-MDR1 cells, and compared with pharmacokinetic data obtained in male C57BL/6 mice. The iP-gp cells formed extremely tight monolayers (>15 000 Ω∙cm2) as compared to the MDCK- MDR1 cells (>250 Ω∙cm2) and displayed lower Papp,a-b values. The efflux ratios obtained with iP-gp and MDCK-MDR1 monolayers correlated with Kp,uu,brain values from the in vivo studies, where compounds with the lowest Kp,uu,brain generally displayed the highest efflux ratios. 12 of the tested compounds displayed a poor BBB penetration in mice as judged by Kp,uu less than 1. Of these compounds, nine compounds were categorized as P-gp substrates in the iP-gp screening, whereas analysis of data estimated in MDCK-MDR1 cells indicated four compounds as potential substrates. The results suggest that the iP-gp cell model may be a sensitive and useful screening tool for drug screening purposes to identify possible substrates of human P-glycoprotein.

Treatment of Homozygous Type II Antithrombin Heparin-Binding Site Deficiency in Pregnancy.

Pregnancy is associated with an increased risk of venous thromboembolism (VTE). Previous VTE and severe thrombophilia are important risk factors. Our case was a 36-year-old woman, gravida 6, para 0, with antithrombin (AT) deficiency caused by a homozygous mutation in the heparin-binding site (HBS). Her history included seven prior VTEs, three early and two late pregnancy losses. She was prophylactically treated with both human plasma-derived AT concentrate (hpATC) and low molecular weight heparin (LMWH), resulting in a successful 6th pregnancy and a healthy live born baby. There is limited evidence and guidance on the management of AT deficiency in pregnancy. Dosing and monitoring of anticoagulants, alone or together with hpATC, must be based on individual risk assessment. The severity of clinical manifestations varies with the type of AT deficiency. Characterization of the AT mutation may aid in the decision-making process and optimize pregnancy outcomes.