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A ring mesh is a large-scale manufacturable structure with versatile applications in architecture and for protective systems. However, the static and dynamic numerical simulation of a large-scale ring mesh is a resource-intensive task due to the many nonlinear contact points between the individual rings. To characterize the rigid body behavior of the ring mesh, in this paper, a representative volume element is loaded under different in-plane directions. The Green-Lagrangian strain tensor components are obtained as a result. An implicit one-step algorithm is used for this dynamic relaxation issue, modified by the use of stiff springs. Static convergence positions of a representative volume element are determined in several multiaxial tensile directions. The obtained deformation parameters can be used to simulate large deformations of large-scaled ring meshes.

In our paper we introduce our model “Structures of Language and Music” and report about a case study in Iceland.We show how language und music education partly draw from similar concepts in either discipline and how theseconcepts may be combined for a deeper understanding of language and music learning both in natural as well asin instructed settings. Looking at data collected in a focus group discussion at the University of Iceland and byobservations in Icelandic music and foreign language classrooms in an inclusive school in Reykjavík we show inthis paper how music and language learning can inspire each other.By understanding the relationship between music and language learning from a more theoretical approachsuggested by our model and its reception by specialists from the music and modern languages departments of theUniversity of Iceland as well as its application to classroom practice, we suggest that our model can make acontribution to language and music education as well as teacher education

Objectives Single umbilical artery (SUA) is associated with congenital malformations in most organ systems, but reported findings have not been consistent. While it has been suggested that genetic and persisting environmental factors influence the development of SUA, it is not known whether there is an increased risk of recurrence in a subsequent pregnancy of the same woman. The aims of this study were to investigate the occurrence of, and risk factors for, SUA in Norway, to assess its association with congenital malformations and trisomies 13, 18 and 21 and to study the risk of recurrence of SUA in subsequent pregnancies. Methods This was a population-based study of all (n = 918 933) singleton pregnancies of > 16 weeks' gestation recorded in the Medical Birth Registry of Norway from 1999 to 2014. To identify risk factors and congenital malformations associated with SUA, generalized estimating equations and logistic regression were used to calculate odds ratios (OR) with 95% CIs. ORs were also calculated for the recurrence of SUA in subsequent pregnancy. Results The occurrence of SUA in our population was 0.46% (4241/918 933). Parity ≥ 4, smoking, maternal pregestational diabetes, epilepsy, chronic hypertension, previous Cesarean delivery and conception by assisted reproductive technology increased the odds of having SUA. There was a particularly strong association between SUA and gastrointestinal atresia or stenosis in the neonate, with ORs of 25.8 (95% CI, 17.0-39.1) and 20.3 (95% CI, 13.4-30.9) for esophageal and anorectal atresia or stenosis, respectively, followed by an OR of 5.9 (95% CI, 1.9-18.5) for renal agenesis. SUA was associated with an up to 7-8 times increased risk of congenital heart defects. There was an association with microcephaly, congenital hydrocephalus and other congenital malformations of the brain and spinal cord. Diaphragmatic hernia, limb reductions and cleft lip or palate had a weaker association with SUA, with ORs ranging from 4.8 to 2.8. The associations with trisomy 18 and 13 were equally strong (OR 14.4 (95% CI, 9.3-22.4) and OR 13.6 (95% CI, 6.7-27.8), respectively), and the risk of trisomy 21 was doubled (OR 2.1 (95% CI, 1.2-3.6)). Pregnancies with SUA, with or without an associated malformation, had a 2-fold increased risk for SUA in a subsequent pregnancy. Conclusions SUA is associated strongly with gastrointestinal atresia or stenosis, suggesting common developmental mechanisms. The increased risk of recurrence of SUA suggests that genetic and/or persisting environmental factors influence the risk. We found that SUA had equally strong associations with trisomies 13 and 18. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Objective To explore risk profiles of the different types of postpartum hemorrhage (PPH >500ml or severe PPH >1500ml) and their recurrence risks in a subsequent delivery. Methods With data from The Medical Birth Registry of Norway and Statistics Norway we performed a population-based cohort study including all singleton deliveries in Norway from 1967–2017. Multilevel logistic regression was used to calculate odds ratio (OR), with 95% confidence interval (CI), with different PPH types (PPH >500ml or PPH >1500ml (severe PPH) combined with retained placenta, uterine atony, obstetric trauma, dystocia, or undefined cause) as outcomes. Result We identified 277 746 PPH cases of a total of 3 003 025 births (9.3%) from 1967 to 2017. Retained placenta (and/or membranes) was most often registered as severe PPH (29.3%). Maternal, fetal, and obstetric characteristics showed different associations with the PPH types. Male sex of the neonate was associated with reduced risk of PPH. This effect was strongest on PPH due to retained placenta (adjusted OR, (aOR): 0.80, 95% CI 0.78–0.82), atony (aOR 0.92, 95% CI: 0.90–0.93) and PPH with undefined cause (aOR 0.96, 95% CI: 0.95–0.97). Previous cesarean section showed a strong association with PPH due to dystocia (aOR of 13.2, 95% CI: 12.5–13.9). Recurrence risks were highest for the same type: PPH associated with dystocia (aOR: 6.8, 95% CI: 6.3–7.4), retained placenta and/or membranes (aOR: 5.9, 95% CI: 5.5–6.4), atony (aOR: 4.0, 95% CI: 3.8–4.2), obstetric trauma (aOR: 3.9, 95% CI: 3.5–4.3) and PPH of undefined cause (aOR: 2.2, 95% CI: 2.1–2.3). Conclusion Maternal, fetal and obstetric characteristics had differential effects on types of PPH. Recurrence differed considerably between PPH types. Retained placenta was most frequently registered with severe PPH, and showed strongest effect of sex; delivery of a boy was associated with lower risk of PPH. Previous cesarean increased the risk of PPH due to dystocia.

Purpose This study examines individual aggregation of postpartum hemorrhage (PPH), paternal contribution and how offspring birthweight and sex influence recurrence of PPH. Further, we wanted to estimate the proportion of PPH cases attributable to a history of PPH or current birthweight. Methods We studied all singleton births in Norway from 1967 to 2017 using data from Norwegian medical and administrational registries. Subsequent births in the parents were linked. Multilevel logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CI) for PPH defined as blood loss > 500 ml, blood loss > 1500 ml, or the need for blood transfusion in parous women. Main exposures were previous PPH, high birthweight, and fetal sex. We calculated adjusted population attributable fractions for previous PPH and current high birthweight. Results Mothers with a history of PPH had three- and sixfold higher risks of PPH in their second and third deliveries, respectively (adjusted OR 2.9; 95% CI 2.9–3.0 and 6.0; 5.5–6.6). Severe PPH (> 1500 ml) had the highest risk of recurrence. The paternal contribution to recurrence of PPH in deliveries with two different mothers was weak, but significant. If the neonate was male, the risk of PPH was reduced. A history of PPH or birthweight ≥ 4000 g each accounted for 15% of the total number of PPH cases. Conclusion A history of PPH and current birthweight exerted strong effects at both the individual and population levels. Recurrence risk was highest for severe PPH. Occurrence and recurrence were lower in male fetuses, and the paternal influence was weak.

Aim We evaluated the role of placental pathology in predicting adverse outcomes for neonates born extremely preterm (EPT) before 28 weeks of gestation. Methods This was a prospective observational study of 123 extremely preterm singletons born in a hospital in western Norway, and the placentas were classified according to the Amsterdam criteria. The associations between histologic chorioamnionitis (HCA), by the presence or the absence of a foetal inflammatory response (FIR+ or FIR−), maternal vascular malperfusion (MVM) as a whole and adverse neonatal outcomes were evaluated by logistic regression analyses. Adverse outcomes were defined as perinatal death, necrotising enterocolitis (NEC), bronchopulmonary dysplasia (BPD), brain pathology by magnetic resonance imaging at term-equivalent age, retinopathy of prematurity and early-onset neonatal sepsis. The results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results HCA was associated with NEC (OR 12.2, 95% CI 1.1 to 137.1). HCA/FIR+ was associated with BPD (OR 14.9, 95% CI 1.8–122.3) and brain pathology (OR 9.8, 95% CI 1.4–71.6), but HCA/FIR− was not. The only neonatal outcome that MVM was associated with was low birthweight. Conclusion Placental histology provided important information when assessing the risk of adverse neonatal outcomes following EPT birth. publishedVersion

Introduction Isolated single umbilical artery (iSUA) refers to single umbilical artery cords with no other fetal malformations. The association of iSUA to adverse outcome of pregnancy has not been consistently reported, and whether iSUA carries increased risk of third stage of labor complications has not been studied. We aimed to investigate the risk of adverse perinatal outcome, third stage of labor complications, and associated placental and cord characteristics in pregnancies with iSUA. A further aim was to assess the risk of recurrence of iSUA and anomalous cord or placenta characteristics in Norway. Material and methods This was a population-based study of all singleton pregnancies with gestational age >16 weeks at birth using data from the Medical Birth Registry of Norway from 1999 to 2014 (n = 918 933). Odds ratios (OR) with 95% confidence intervals were calculated for adverse perinatal outcome (preterm birth, perinatal and intrauterine death, low Apgar score, transferral to neonatal intensive care ward, placental and cord characteristics [placental weight, cord length and knots, anomalous cord insertion, placental abruption and previa]), and third stage of labor complications (postpartum hemorrhage and the need for manual placental removal or curettage) in pregnancies with iSUA, and recurrence of iSUA using generalized estimating equations and logistic regression. Results Pregnancies with iSUA carried increased risk of adverse perinatal outcome (OR 5.06, 95% confidence interval [CI] 4.26-6.02) and perinatal and intrauterine death (OR 5.62, 95% CI 4.69-6.73), and a 73% and 55% increased risk of preterm birth and small-for-gestational-age neonate, respectively. The presence of iSUA also carried increased risk of a small placenta, placenta previa and abruption, anomalous cord insertion, long cord, cord knot and third stage of labor complications. Women with iSUA, long cord or anomalous cord insertion in one pregnancy carried increased risk of iSUA in the subsequent pregnancy. Conclusions The presence of ISUA was associated with a more than five times increased risk of intrauterine and perinatal death and with placental and cord complications. The high associated risk of adverse outcome justifies follow up with assessment of fetal wellbeing in the third trimester, intrapartum surveillance and preparedness for third stage of labor complications.

Purpose: Speckle tracking echocardiography is a promising method for assessment of myocardial function in fetal and neonatal hearts, but further studies are necessary to validate and optimize the settings for use in fetal cardiology. Previous studies have shown that the definition of the region of interest (ROI) affects strain values in adults. The aim of this study was to investigate how different widths of ROI influences measurements of four-chamber longitudinal systolic strain in fetuses late in pregnancy.Methods: Thirty-one singleton, healthy fetuses born to healthy mothers underwent an echocardiographic examination during gestational week 37. Speckle tracking was performed with two different settings for ROI width; the narrowest and second most narrow, provided both widths were assessed as suitable for the myocardial wall thickness of the fetus. Results: We found an inverse correlation between the ROI width and the strain values. Four-chamber longitudinal strain changed from -20.7 ± 3.6% to -18.0 ± 4.4% (pConclusions: Different widths of ROI influenced the strain measurements significantly in the fetal heart, comparable to what has been reported in adults. A standardization of the ROI setting could improve the interpretation, and reduce variability in fetal strain measurements.

Background Sleep and physical activity changes are common in pregnancy, but longitudinal data starting before conception are scarce. Our aim was to determine the changes of the daily total sleep time (TST) and physical activity duration (PAD) from before conception to end of pregnancies in respect of pregestational maternal factors. Methods This longitudinal observational study formed part of the CONIMPREG research project and recruited healthy women planning to become pregnant. Sleep and physical activity were recorded around-the-clock for ≥4 days via actigraphy before conception and during each trimester of pregnancy. Data were adjusted according to pregestational maternal body composition, parity and age. Results Among 123 women with eligible data, the unadjusted mean (95% confidence interval) TST increased from 415.3 min (405.5–425.2 min) before conception to 458.0 min (445.4–470.6 min) in the 1st trimester, remaining high through the 2nd and 3rd trimesters. Variation was substantial before conception (±2SD range: 307–523 min). The unadjusted mean PAD before conception was 363.7 min (±2SD range: 120–608 min), decreasing sharply to 262.1 min in the first trimester and more gradually thereafter. Vigorous and moderate activity decreased more than light activity. TST and PAD were significantly associated with age, parity, and pregestational body fat percentage; lean body mass was negatively correlated with TST. Results were generally unaffected by seasonal variations. Conclusion Marked variations were found in pregestational TST and PAD. Healthy women slept ≥30 min longer during pregnancy, while PAD decreased by ≥ 90 min in early pregnancy and continued to decrease thereafter.

Introduction Studies on the family aggregation of postpartum hemorrhage (PPH) are scarce and with inconsistent results, and to what extent current birthweight influences recurrence between relatives remains to be studied. Further, family aggregation of PPH has been studied from an individual, but not from a public heath perspective. We aimed to investigate family aggregation of PPH in Norway, how birthweight influences these effects, and to estimate the proportion of PPH cases attributable to a family history of PPH and current birthweight. Material and methods Using data from the Medical Birth Registry of Norway, Statistics Norway, and Central Population Registry of Norway we identified individuals as newborns, parents, grandparents, and full and half-siblings, and studied 1 002 687 mother–offspring, 841 164 father–offspring, and 761 011 both-parents–offspring pairs. We used multilevel logistic regression to calculate odds ratios (OR) with 95% CI. Results If the birth of the mother but not of the father involved PPH, then the OR of PPH (>500 mL) in the next generation was 1.44 (95% CI 1.39–1.49). If the birth of the father but not of the mother involved PPH, then OR was 1.12 (95% CI 1.08–1.16). These effects were stronger in severe PPH. Recurrence between siblings was highest between full sisters (OR 1.47, 95% CI 1.41–1.52), followed by maternal half-sisters, paternal half-sisters, and partners of full brothers. A family history of PPH or birthweight of 4000 g or more accounted for ≤5% and 15% of the total number of PPH cases, respectively. Conclusions A history of PPH in relatives influenced the recurrence risk of PPH in a dose–response pattern consistent with the anticipated proportion of shared genes. The recurrence was highest through the maternal line. publishedVersion

INTRODUCTION Despite adequate glycemic control, the risks of fetal macrosomia and perinatal complications are increased in diabetic pregnancies. Adjustments of the umbilical venous distribution, including increased ductus venosus shunting, can be important fetal compensatory mechanisms, but the impact of pregestational diabetes on umbilical venous and ductus venosus flow is not known. MATERIAL AND METHODS In this prospective study, 49 women with pregestational diabetes mellitus underwent monthly ultrasound examinations from gestational week 20 to 36. The blood velocity and the mean diameters of the umbilical vein and ductus venosus were used for calculating blood flow volumes. The development of the umbilical venous flow, ductus venosus flow and ductus venosus shunt fraction (% of umbilical venous blood shunted through the ductus venosus) was compared with a reference population, and the effect of HbA1c on the ductus venosus flow was assessed. RESULTS The umbilical venous flow was larger in pregnancies with pregestational diabetes mellitus than in low-risk pregnancies (p

Introduction The new Holter monitoring technology enables long-term electrocardiographic recording of the fetal heart rate without discomfort for the mother. The aim of the study was to assess the feasibility of a fetal Holter monitor. This technology was further used to study fetal heart rate outside the hospital setting during normal daily activities and to test the hypothesis that uterine activity during pregnancy influences fetal heart rate. Material and methods Prospective observational study including 12 healthy pregnant women at 20–40 weeks of gestation. Data were collected using the Monica AN24 system. Outcome measures were fetal heart rate, maternal heart rate, and uterine activity categorized according to the strength of the electrohysterographic signal. Results The recordings had a median length of 18.8 h, and fetal heart rate and maternal heart rate were obtained with success rates of 73.1 and 99.9%, respectively. Uterine activity was found to affect fetal heart rate in all participants. Compared with the basal tone and mild levels of uterine activity, moderate and strong levels of uterine activity were associated with increases in fetal heart rate of 4.0 and 5.7 beats/min, respectively. At night, the corresponding increases were 4.9 and 7.6 beats/min. Linear correlations were found between maternal heart rate and fetal heart rate in 11 of the 12 cases, with a mean coefficient beta of 0.189. Both maternal heart rate and fetal heart rate exhibited a diurnal pattern, with lower heart rates being recorded at night. Conclusions Uterine activity during pregnancy is associated with a graded response in fetal heart rate and may represent a physiological challenge for the development and adaptation of the fetal cardiovascular system.

Adoptive transfer of T regulatory cells (Treg) has been successfully exploited in the context of graft-versus-host disease, transplantation, and autoimmune disease. For the majority of applications, clinical administration of Treg requires laborious ex vivo expansion and typically involves open handling for culture feeds and repetitive sampling. Here we show results from our approach to translate manual Treg manufacturing to the fully closed automated CliniMACS Prodigy® system reducing contamination risk, hands-on time, and quality variation from human intervention. Polyclonal Treg were isolated from total nucleated cells obtained through leukapheresis of healthy donors by CD8+ cell depletion and subsequent CD25high enrichment. Treg were expanded with the CliniMACS Prodigy® device using clinical-grade cell culture medium, rapamycin, IL-2, and αCD3/αCD28 beads for 13–14 days. We successfully integrated expansion bead removal and final formulation into the automated procedure, finalizing the process with a ready to use product for bedside transfusion. Automated Treg expansion was conducted in parallel to an established manual manufacturing process using G-Rex cell culture flasks. We could prove similar expansion kinetics leading to a cell yield of up to 2.12 × 109 cells with the CliniMACS Prodigy® and comparable product phenotype of >90% CD4+CD25highCD127lowFOXP3+ cells that had similar in vitro immunosuppressive function. Efficiency of expansion bead depletion was comparable to the CliniMACS® Plus system and the final ready-to-infuse product had phenotype stability and high vitality after overnight storage. We anticipate this newly developed closed system expansion approach to be a starting point for the development of enhanced throughput clinical scale Treg manufacture, and for safe automated generation of antigen-specific Treg grafted with a chimeric antigen receptor (CAR Treg).

Circadian rhythmicity is fundamental to human physiology, and is present even during fetal life in normal pregnancies. The impact of maternal endocrine disease on the fetal circadian rhythm is not well understood. The present study aimed to determine the fetal circadian rhythm in pregnancies complicated by pregestational diabetes mellitus (PGDM), compare it with a low-risk reference population, and identify the effects of maternal glycemic control and morning cortisol concentrations. Long-term fetal electrocardiogram recordings were made in 40 women with PGDM at 28 and 36 weeks of gestation. Two recordings were made in 18 of the women (45.0%) and one recording was made in 22 (55.0%). The mean fetal heart rate (fHR) and the fHR variation (root mean square of squared differences) were extracted in 1-min epochs, and circadian rhythmicity was detected by cosinor analysis. The study cohort was divided based on HbA1c levels and morning cortisol concentrations. Statistically, significant circadian rhythms in the fHR and the fHR variation were found in 45 (100%) and 44 (95.7%) of the 45 acceptable PGDM recordings, respectively. The rhythms were similar to those of the reference population. However, there was no statistically significant population-mean rhythm in the fHR among PGDM pregnancies at 36 weeks, indicating an increased interindividual variation. The group with higher HbA1c levels (6.0%) had no significant population-mean fHR rhythm at 28 or 36 weeks, and no significant fHR-variation rhythm at 36 weeks. Similarly, the group with a lower morning cortisol concentration (≤8.8 µg/dl) had no significant population-mean fHR-variation rhythm at 28 and 36 weeks. These findings indicate that individual fetal rhythmicity is present in pregnancies complicated by PGDM. However, suboptimal maternal glycemic control and a lower maternal morning cortisol concentration are associated with a less-well-synchronized circadian system of the fetus.

Background Pregestational diabetes is associated with fetal macrosomia, and umbilical perfusion of the fetal liver has a role in regulating fetal growth. We therefore hypothesized that pregestational diabetes alters fetal liver blood flow depending on degree of glycemic control. Methods In a prospective study, 49 women with pregestational diabetes underwent monthly ultrasound examinations during 24-36 gestational weeks. Blood flow was determined in the umbilical vein, ductus venosus and portal vein, and blood velocity was measured in the left portal vein, the latter reflecting the watershed between splanchnic and umbilical flow. The measurements were compared with reference values by z-score statistics, and the effect of HbA 1c assessed. Results The umbilical venous flow to the liver (z-score 0.36, p = 0.002), total venous liver flow (z-score 0.51, p1C . Conclusions In spite of increased umbilical blood distribution to the fetal liver, graded according to glycemic control, the total venous liver flow did not match third trimester fetal growth in pregnancies with pregestational diabetes, thus contributing towards increased perinatal risks and possibly altered liver function with long-term metabolic consequences.

INTRODUCTION Fetal biometry is used for determining gestational age and estimated date of delivery (EDD). However, the accuracy of the EDD depends on the assumed length of pregnancy included in the calculation. This study aimed at assessing the actual pregnancy length and accuracy of EDD prediction based on fetal head circumference measured at the second trimester. MATERIAL AND METHODS This was a population-based observational study with the following inclusion criteria: singleton pregnancy, head circumference dating in the second trimester, spontaneous onset or induction of delivery ≥ 294 days of gestation, live birth. The EDD was set anticipating a pregnancy length of 282 days. Bias in the prediction of EDD was defined as the difference between the actual date of birth and the EDD. RESULTS Head circumference measurements were available for 21 451 pregnancies. Ultrasound-dated pregnancies had a median pregnancy length of 283.03 days, corresponding to a method bias of 1.03 days (95% CI; 0.89-1.16). This bias was dependent on the head circumference at dating, ranging from -1.58 days (95% CI; -3.54 to 1.12) to 3.42 days (95% CI; 1.98-4.31). The median pregnancy length, based on the last menstrual period of women with a regular menstrual cycle (n = 12 985), was 283.15 days (95% CI; 282.91-283.31). A total of 5685 (22.9%, 95% CI; 22.4% to 23.4%) and 886 women (3.6%, 95% CI; 3.3%-3.8%) were still pregnant 7 and 14 days after the EDD, respectively. CONCLUSIONS Second trimester head circumference measurements can be safely used to predict EDD. A revision of the pregnancy length to 283 days will reduce the bias of EDD prediction to a level comparable with other methods.

INTRODUCTION The objective of this study was to describe the QRS complex of the fetal electrocardiogram (fECG) in relation to fetal presentation, and explore the effect of abnormal QRS on automated ST-interval analysis (STAN). MATERIAL AND METHODS A case-control study was carried out at a University Hospital in Norway, between the years of 2004-2008. High-risk singleton deliveries with a gestational age >35(+6) weeks, were monitored with cardiotocography and STAN. Cases included breech presentations (n = 433) and controls included cephalic presentations (n = 433). The main outcome measures were QRS-complex abnormalities and fECG abnormalities. RESULTS An abnormal QRS complex was found in 13.9% of the cases and 16.6% of the controls (p = 0.257). Split R (8.4%) and deep S (8.2%) were the most common abnormalities, and deep Q (4.4% vs. 0.7%, p ≤ 0.001) and split Q (1.8% vs. 0, p ≤ 0.005) were more common in breech than in cephalic presentations. QRS abnormalities impacted on the fECG in 114/866 (13.2%) of the total population. The most common finding was an ambiguous placement of R and S in cases of a split vector (n = 112, 12.9%). Deviance of the ECG baseline above null occurred less frequently (n = 33, 3.8%), and was more common in breech presentation (5.3 vs. 2.3%, p = 0.021). ST events due to an erroneous identification of the QRS vectors and/or a misplacement of the ECG baseline were found in 26 (3.0%) fetuses, with no significant difference in frequency between cases and controls. CONCLUSIONS The appearance of the QRS complex of fECG is dependent upon the fetal presentation. QRS abnormalities impact automated fECG tracing and subsequent ST analysis. Clinicians should be aware of this finding in clinical practice.

AIM The knowledge on biological rhythms is rapidly expanding. We aimed to define the longitudinal development of the daily (24-hour) fetal heart rate rhythm in an unrestricted, out-of-hospital setting and to examine the effects of maternal physical activity, season and fetal sex. METHODS We recruited 48 women with low-risk singleton pregnancies. Using a portable monitor for continuous fetal electrocardiography, fetal heart rate recordings were obtained around gestational weeks 24, 28, 32 and 36. Daily rhythms in fetal heart rate and fetal heart rate variation were detected by cosinor analysis; developmental trends were calculated by population-mean cosinor and multilevel analysis. RESULTS For the fetal heart rate and fetal heart rate variation, a significant daily rhythm was present in 122/123 (99.2%) and 116/121 (95.9%) of the individual recordings respectively. The rhythms were best described by combining cosine waves with periods of 24 and 8 hours. With increasing gestational age, the magnitude of the fetal heart rate rhythm increased, and the peak of the fetal heart rate variation rhythm shifted from a mean of 14:25 (24 weeks) to 20:52 (36 weeks). With advancing gestation, the rhythm-adjusted mean value of the fetal heart rate decreased linearly in females (P

Objectives To determine risk factors for short and long umbilical cord, entanglement and knot. Explore their associated risks of adverse maternal and perinatal outcome, including risk of recurrence in a subsequent pregnancy. To provide population based gestational age and sex and parity specific reference ranges for cord length. Design Population based registry study. Setting Medical Birth Registry of Norway 1999–2013. Population All singleton births (gestational age>22weeks

Fetoplacental Doppler abnormalities have been associated with increased neonatal mortality and morbidity. This study evaluated the associations between prenatal Doppler assessments and neonatal mortality and morbidity in premature infants born small for gestational age or after pre-eclampsia.This was a population-based study of infants born alive at 22(0) -33(6) weeks of gestation, a birthweight10th percentile for gestational age and/or maternal pre-eclampsia. Doppler assessments of the umbilical artery, middle cerebral artery and ductus venosus were evaluated in 127, 125 and 95 cases, respectively. Circulatory compromise was defined as absent or reversed end-diastolic velocity in the umbilical artery (AREDF), middle cerebral artery pulsatility index2.5 percentile for gestational age and ductus venosus pulsatility index for veins97.5 percentile.AREDF was present in 28% of the infants. This was associated with increased frequencies of neonatal sepsis and necrotising enterocolitis after adjusting for gestational age. Abnormal ductus venosus pulsatility index for veins was associated with increased risk of neonatal sepsis, but only in combination with AREDF. These associations were only present when gestational age was28 weeks.AREDF was associated with increased neonatal morbidity in premature infants born small for gestational age or after pre-eclampsia.

Objective To determine the electrocardiographic performance and neonatal outcome of pregnancies with breech presentation and planned vaginal delivery monitored with ST-waveform analysis (STAN). Design Prospective observational study. Setting University hospital, Norway; 2004–2008. Population Singleton pregnancies with a gestational age above 35 + 6 weeks, breech presentation, selected for vaginal delivery and monitored with STAN. Methods Common clinical guidelines for STAN monitoring were used. An experienced neonatologist graded the symptoms of neonatal encephalopathy. The outcome was compared with STAN-monitored high-risk deliveries in a vertex presentation (n = 5569) using logistic regression analysis. Main outcome measure Frequency of ST events, indications of intervention for fetal distress, and neonatal morbidity and mortality. Results Breech presentation occurred in 750 of 23 219 (3.2%) deliveries, 625 (83%) of which were selected for vaginal delivery. Intrapartum monitoring by STAN was performed in 433 (69%). Compared with vertex presentations, fetuses in breech presentation had a lower risk of baseline T/QRS rise during labour [odds ratio (OR) = 0.7, 95% confidence interval (95% CI) = 0.7–0.9, P = 0.003] and a higher risk for intervention as a result of preterminal cardiotocogram (OR = 2.9, 95% CI = 1.6–5.9, P = 0.001). The risks of perinatal mortality (OR = 1.8, 95% CI = 0.2–15, P = 0.6), cord metabolic acidosis (OR = 0.8, 95% CI = 0.2–3.2, P = 0.7) and moderate or severe neonatal encephalopathy (OR = 1.8, 95% CI = 0.5–6.2, P = 0.3) did not differ significantly between breech and vertex deliveries. Conclusion STAN can be used for the surveillance of breech presentations selected for vaginal delivery with an acceptable neonatal outcome. The electrocardiogram (ECG) pattern during labour varies with the fetal presentation.

Five randomized controlled trials have been published on intrapartum fetal heart rate monitoring with ST analysis of the fetal electrocardiogram, but the debate on its usefulness has not yet been ended. We consider ST analysis a useful and cost-effective addition to conventional fetal heart rate monitoring. We will provide support for this opinion by discussing the pathophysiology of ST changes in relation to fetal asphyxia, the results of the randomized controlled trials and numerous meta-analyses of these randomized controlled trials and trends in fetal outcome in hospitals in different countries following the introduction of the ST technology in the labor ward.

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.

Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cell-released soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and down-regulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells.

Objective To evaluate the clinical use of ST analysis (STAN) for intrapartum monitoring of high-risk pregnancies. Design Prospective observational study. Setting University hospital, Norway, 2004–2008. Population Singleton pregnancies with a gestational age above 35+6 weeks. Methods Analysis of maternal and neonatal outcomes for all deliveries according to the method of intrapartum monitoring. Main outcome measures Prevalence of cord metabolic acidosis (pH 12 mmol/L). Results Of 23 203 deliveries, 6010 (25.9%) were monitored with STAN. Fetal blood sampling was performed in 146 (2.4%) of the 6010 cases. During the study period, the prevalence of cord metabolic acidosis and moderate cord acidosis (pH

The health authorities of Stockholm county recently published a Health Technology Assessment report: "Fetal monitoring with computerized STAN analysis during labor - a systematic review" with the aim to ensure that high quality research information on costs, effectiveness and broader impact of health technologies is analysed and presented in the most efficient way for those who use, manage and work in this field. The report claims to analyse available research in relation to ST interval analysis of fetal electrocardiogram (STAN) and concludes that scientific evidence for advantages of the STAN technology for maternal and fetal outcome was insufficient and that clinical use cannot be recommended and should be restricted to research protocols. The Norwegian reference group for fetal surveillance points out that the report suffers from two insufficiencies: selection bias by not providing a complete collection of the evidence for the clinical performance of the STAN technology and, secondly, that it does not provide evidence-based alternative methods.

OBJECTIVES: Serial Doppler measurements of the ductus venosus are used increasingly for monitoring fetuses at risk of hemodynamic compromise, but existing reference ranges are based on cross-sectional studies and thus are less suitable for comparison with serial measurements. We aimed to establish longitudinal reference ranges for ductus venosus flow velocities and waveform indices and to provide the necessary terms for calculating conditional reference ranges for serial measurements. METHODS: This was a longitudinal study of 160 low-risk pregnancies. Pulsed Doppler ultrasound was used to record ductus venosus blood flow velocities at 4-week intervals from 20-22 weeks of gestation onwards. RESULTS: With a success rate of 93%, 547 measurements (four or five in each fetus) were used to establish reference ranges. The time-averaged maximum velocity was 50 cm/s at 21 weeks of gestation, increased to 60 cm/s at 32 weeks, and remained so until term. Similarly, the peak systolic velocity increased from 59 cm/s at 21 weeks to 71 cm/s at 31 weeks and remained so until term. The end-diastolic velocity showed a continuous increase from 31 cm/s at 21 weeks to 43 cm/s at 40 weeks. The pulsatility index for veins decreased from 0.57 at 21 weeks to 0.44 at 40 weeks. When conditioned by a previous measurement, the reference ranges for the next observation became narrower and commonly shifted compared with those of the entire population. CONCLUSION: The new longitudinal reference ranges presented here reflect the development of the ductus venosus flow velocities and velocity indices and are thus appropriate for serial measurements, particularly if conditional terms are included

Objective To determine the degree of ductus venosus (DV) shunting in fetuses with intrauterine growth restriction (IUGR) and the effect of various degrees of umbilical circulatory compromise. Methods This was a cross-sectional observational study. Sixty-four fetuses with IUGR (estimated weight ≤ 2.5th percentile) underwent ultrasound examination. The diameter, velocity, and blood flow were determined in the DV and intra-abdominal umbilical vein (UV), and the fraction of shunting and DV : UV diameter ratios were calculated. Placental compromise was classified according to either normal umbilical artery (UA) pulsatility index (PI), UA-PI > 97.5th percentile, or absent or reversed end-diastolic flow velocity (A/REDV). Regression analysis was used to construct mean values, and SD scores were used to determine differences compared with a reference population (n = 212) after ln- or power-transformation. Results In the 64 growth-restricted fetuses, the average DV shunting was 39% compared with 25% in the reference group (overall P 97.5th percentile, and A/REDV were 31%, 35%, and 57%, respectively. Fetuses with IUGR and normal UA-PI (SD score: mean, 0.48; 95% CI, 0.04–0.92) did not shunt significantly more than did the reference fetuses (SD score: mean, 0.0; 95% CI, − 0.15 to 0.15), but those with UA-PI > 97.5th percentile (SD score: mean, 0.85; 95% CI, 0.41–1.29), and particularly those with A/REDV (SD score: mean, 1.56; 95% CI, 1.0–2.12) did shunt significantly more. With more DV shunting, these fetuses distributed correspondingly less umbilical blood to the liver, one of the mechanisms being a lower perfusion pressure as reflected in the lower DV blood velocity (P < 0.0001). Conclusions DV shunting is higher and the umbilical blood flow to the liver is less in fetuses with IUGR, particularly in those with the most severe umbilical hemodynamic compromise. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.

To investigate pancreatic histopathology in relation to islet function in type 2 diabetes, pancreatic tissue was examined at disease onset and after death in the genetically diabetic Chinese hamster CHIG/Han subline. The pancreatic islets displayed vacuolation, intraislet fibrosis, variable stages of degranulation, and beta-cell necrosis, but no insulitis. These lesions were associated with changes in immunostaining of major islet peptides, impaired glucose-stimulated (10 mM) insulin secretion, reduced islet insulin content, and the severity of hyperglycemia. The exocrine pancreas was characterized by peri- and intrapancreatic fat and mononuclear cell infiltration. Biopsy of the pancreas had a marked effect on plasma glucose such that at 2 weeks after excision, in 9 and 18% of the severely hyperglycemic hamsters, plasma glucose levels decreased to

We reappraised the five randomized controlled trials that compared cardiotocography plus ECG ST interval analysis (CTG+ST) vs. cardiotocography. The numbers enrolled ranged from 5681 (Dutch randomized controlled trial) to 799 (French randomized controlled trial). The Swedish randomized controlled trial (n = 5049) was the only trial adequately powered to show a difference in metabolic acidosis, and the Plymouth randomized controlled trial (n = 2434) was only powered to show a difference in operative delivery for fetal distress. There were considerable differences in study design: the French randomized controlled trial used different inclusion criteria, and the Finnish randomized controlled trial (n = 1483) used a different metabolic acidosis definition. In the CTG+ST study arms, the larger Plymouth, Swedish and Dutch trials showed lower operative delivery and metabolic acidosis rates, whereas the smaller Finnish and French trials showed minor differences in operative delivery and higher metabolic acidosis rates. We conclude that the differences in outcomes are likely due to the considerable differences in study design and size. This will enhance heterogeneity effects in any subsequent meta-analysis. publishedVersion

Objective To assess the effect of the time interval from indication of hypoxia to delivery on neonatal outcome in high-risk pregnancies monitored with cardiotocography (CTG) and ST-waveform analysis. Design Prospective observational study. Setting University hospital, Norway, 2004–08. Population Singleton high-risk births with a gestational age above 35+6 weeks, monitored with CTG and ST-waveform analysis. Methods Logistic regression analysis and Kaplan–Meier survival plots. Main outcome measure Neonatal morbidity in relation to the rapidity of intervention. Results Of 6010 deliveries monitored with ST-waveform analysis, 1131 (19%) had an indication to intervene for fetal distress according to clinical guidelines. Those fetuses were at increased risk of an adverse neonatal outcome, and if delivered later than 20 min after the indication of hypoxia their risk increased further; i.e. transfer to the neonatal intensive care unit (NICU) from an odds ratio of 1.6 (95% confidence interval 1.2–2.2) to an odds ratio of 3.3 (95% confidence interval 2.5–4.3). The indication-to-delivery interval was longer for neonates with a 5-min Apgar score of

Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically.

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.

The health authorities of Stockholm county recently published a Health Technology Assessment report: "Fetal monitoring with computerized STAN analysis during labor - a systematic review" with the aim to ensure that high quality research information on costs, effectiveness and broader impact of health technologies is analysed and presented in the most efficient way for those who use, manage and work in this field. The report claims to analyse available research in relation to ST interval analysis of fetal electrocardiogram (STAN) and concludes that scientific evidence for advantages of the STAN technology for maternal and fetal outcome was insufficient and that clinical use cannot be recommended and should be restricted to research protocols. The Norwegian reference group for fetal surveillance points out that the report suffers from two insufficiencies: selection bias by not providing a complete collection of the evidence for the clinical performance of the STAN technology and, secondly, that it does not provide evidence-based alternative methods.

Background The human lymphocyte antigen (HLA) encoded BAT3/BAG6 recently attracted interest as a regulator of protein targeting and degradation, a function that could be exerted in the cytosol and in the nucleus. The BAT3 gene was described to consist of 25 exons. Diversity of transcripts can be generated by alternative RNA splicing, which may control subcellular distribution of BAT3. Methodology/Principal Findings By cDNA sequencing we identified a novel alternatively spliced sequence of the BAT3 gene located between exons 11 and 12, which was designated as exon 11B. Using PCR and colony hybridization we identified six cDNA variants, which were produced by RNA splicing of BAT3 exons 5, 11B and 24. In four examined cell types the content of BAT3 splice variants was examined. Most of the cDNA clones from monocyte-derived dendritic cells contain exon 11B, whereas this sequence was almost absent in the B lymphoma Raji. Exon 5 was detected in most and exon 24 in approximately half of the cDNA clones. The subcellular distribution of endogenous BAT3 largely correlates with a cell type specific splicing pattern. In cells transfected with BAT3 variants, full-length and Δ24 BAT3 displayed nearly exclusive nuclear staining, whereas variants deleted of exon 11B showed substantial cytosolic expression. We show here that BAT3 is mainly expressed in the cytosol of Raji cells, while other cell types displayed both cytosolic and nuclear staining. Export of BAT3 from the nucleus to the cytosol is inhibited by treatment with leptomycin B, indicating that the Crm1 pathway is involved. Nuclear expression of BAT3 containing exon 11B suggests that this sequence plays a role for nuclear retention of the protein. Conclusions/Significance Cell type-specific subcellular expression of BAT3 suggests distinct functions in the cytosol and in the nucleus. Differential expression of BAT3 variants may reconcile the multiple roles described for BAT3.

To evaluate the clinical use of ST analysis (STAN) for intrapartum monitoring of high-risk pregnancies.Prospective observational study.University hospital, Norway, 2004-2008.Singleton pregnancies with a gestational age above 35(+6) weeks.Analysis of maternal and neonatal outcomes for all deliveries according to the method of intrapartum monitoring.Prevalence of cord metabolic acidosis (pH7.05, extracellular fluid base deficit (extracellular fluid)12 mmol/L).Of 23 203 deliveries, 6010 (25.9%) were monitored with STAN. Fetal blood sampling was performed in 146 (2.4%) of the 6010 cases. During the study period, the prevalence of cord metabolic acidosis and moderate cord acidosis (pH7.15) decreased in STAN-monitored deliveries from 1.4 to 0.3% (p = 0.01) and from 16.4 to 11.7% (p = 0.001), respectively. The prevalence of moderate and severe neonatal encephalopathy was 0.38%. In the birth population, the proportion of cesarean deliveries decreased from 10.1 to 8.8%. The risk of emergency cesarean section after STAN monitoring compared with those monitored with auscultation/cardiotocography was high (odds ratio 5.4, 95% confidence interval = 4.9-6.1) but remained stable during the study period.ST analysis is a useful tool for identification of fetuses at risk of intrapartum hypoxia. Despite the restricted use of fetal blood sampling, we found a low proportion of cord metabolic acidosis and newborn morbidity.

Eighty to 85% of the venous perfusion to the fetal liver is from the umbilical vein, the rest from the portal vein. Umbilical venous flow to the liver is essential for intrauterine growth, and is impaired in placental insufficiency. We hypothesized that in growth-restricted fetuses portal blood flow compensates for insufficient umbilical blood flow to the liver. In 29 fetuses with fetal growth restriction (estimated fetal weightor =5th percentile), we used ultrasound to measure blood flows in the umbilical vein, ductus venosus, left portal vein, and main portal stem. Compared with normal fetuses, both absolute and normalized total venous liver blood flows were reduced in growth-restricted fetuses, related to the degree of placental compromise and equally affecting both liver lobes. However, portal replaced umbilical flow to the right lobe, in a manner graded according to placental vascular resistance; in extreme cases, the right lobe received no umbilical perfusion. In fetal growth restriction, the liver suffers from venous hypoperfusion, and portal blood partially replaces umbilical flow to the right lobe; this will result in right liver lobe hypoxemia. This striking prioritization in nutrient delivery of left over right lobes suggests an adaptive response to poor placental perfusion that may have functional consequences.

Recent data suggest that umbilical venous perfusion of the fetal liver has an important influence on fetal growth and postnatal liver function, and that maternal factors in late pregnancy modify this circulation. In a longitudinal study of 160 low-risk pregnancies, we determined how umbilical and portal venous blood flows to the fetal liver changed during gestation, and examined the hypothesis that maternal body mass index and pregnancy weight gain influenced fetal liver blood flows. We measured blood flows in the umbilical and portal veins, left portal branch, and ductus venosus using ultrasound. Normalizing for estimated fetal weight, fetal liver total venous blood flow fell from 84 to 57 mL. min(-1). kg(-1) during 21-39 wk of gestation; toward term the portal contribution increased (from 14 to 20%) and the umbilical contribution fell, whereas distribution between the left and right liver lobes was stable, 60%/40%. Greater flow of nutrient-rich umbilical venous blood to the liver was associated with higher birth weight and neonatal ponderal index. Maternal body mass index was not related to fetal liver blood flows, but low pregnancy weight gain strongly influenced flow distribution between the right and left liver lobes, sparing the left lobe and increasing the difference between lobes by 16%.

Objectives The left portal vein represents a watershed area in the fetal circulation and the change of flow direction is a suggested marker of circulatory compromise. Our aim was to study the left portal vein of uncompromised human pregnancies and establish reference ranges. Methods One hundred and sixty low-risk pregnant women were recruited to a longitudinal study that included four to five Doppler measurements at monthly intervals during the second half of pregnancy. Results Based on 554 Doppler recordings we found time-averaged maximum flow velocities increasing from a mean of 10.6 cm/s to 14.2 cm/s during 21–31 weeks of gestation, remaining stable until 37 weeks and decreasing towards term. Intermittent flow reversal occurred during fetal respiratory movements, and continuous flow reversal was seen in 2/160 fetuses close to delivery. Conclusions We propose time-averaged maximum blood velocity measurement for quantification of the watershed phenomenon in the left portal branch, and have provided reference ranges for single observations and serial measurements. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.

Objectives The umbilical vein is the major source of blood for the fetal liver, but portal blood, which has not been measured directly in human fetuses, probably constitutes a physiologically important contribution. We aimed to establish a method for measuring blood flow in the fetal portal vein and to produce longitudinal reference ranges for diameter, blood flow velocities and volume blood flow during the second half of pregnancy. Methods After a pilot project to develop the measuring technique, 160 low-risk pregnant women were recruited to a longitudinal study that included ultrasound examinations at 4–5-week intervals starting at 20–22 weeks of gestation. The inner diameter (D) of the vessel was measured with a perpendicular insonation angle, and the time-averaged maximum blood velocity (TAMXV) and weighted mean velocity (VWMEAN) were recorded with an insonation directed along the long axis of the vessel. Portal flow was calculated as: Q = π(D/2)2 × h × TAMXV (where h is a velocity profile parameter and equals 0.5). Portal flow was normalized for estimated fetal weight based on birth-weight percentiles. Results The portal vein could be visualized and measured in 558/593 (94%) cases. Blood flow was pulsatile. D and TAMXV doubled during the second half of pregnancy (21–39 weeks), from 1.5 to 3.4 mm and from 8.4 to 14.9 cm/s, respectively. Correspondingly, the portal flow increased from 5 to 41 mL/min, and from 10 to 13 mL/min/kg when normalized for fetal weight. Similar results were achieved for VWMEAN. Conclusion Portal flow can be measured with a standardized technique. It increases during the second half of pregnancy, even when normalized for fetal weight, suggesting that it has increasing importance in the fetal liver circulation. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.