Rosie Hospital

STUDY QUESTION: What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER: Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY: The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION: We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS: Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER: NA.

Abstract Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age 1 . Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine 2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating.

OBJECTIVE: To establish whether the timing of delivery between 37 and 42 weeks gestation influences neonatal respiratory outcome and thus provide information which can be used to aid planning of elective delivery at term. DESIGN: All cases of respiratory distress syndrome or transient tachypnoea at term requiring admission to the neonatal intensive care unit were recorded prospectively for nine years. SETTING: Rosie Maternity Hospital, Cambridge. SUBJECTS: During this time 33,289 deliveries occurred at or after 37 weeks of gestation. MAIN OUTCOME MEASURES: This information enabled calculation of the relative risk of respiratory morbidity for respiratory distress syndrome or transient tachypnoea in relation to mode of delivery and onset of parturition for each week of gestation at term. RESULTS: The incidence of respiratory distress syndrome at term was 2.2/1000 deliveries (95% CI; 1.7-2.7). The incidence of transient tachypnoea was 5.7/1000 deliveries (95% CI; 4.9-6.5). The incidence of respiratory morbidity was significantly higher for the group delivered by caesarean section before the onset of labour (35.5/1000) compared with caesarean section during labour (12.2/1000) (odds ratio, 2.9; 95% CI 1.9-4.4; P < 0.001), and compared with vaginal delivery (5.3/1000) (odds ratio, 6.8; 95% CI 5.2-8.9; P < 0.001). The relative risk of neonatal respiratory morbidity for delivery by caesarean section before the onset of labour during the week 37+0 to 37+6 compared with the week 38+0 to 38+6 was 1.74 (95% CI 1.1-2.8; P < 0.02) and during the week 38+0 to 38+6 compared with the week 39+0 to 39+6 was 2.4 (95% CI 1.2-4.8; P < 0.02). CONCLUSIONS: A significant reduction in neonatal respiratory morbidity would be obtained if elective caesarean section was performed in the week 39+0 to 39+6 of pregnancy.

OBJECTIVES: Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. METHODS: We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. RESULTS: Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. CONCLUSIONS: Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.

Angiogenesis is important in the pathophysiology of endometriosis, a condition characterized by implantation of ectopic endometrium in the peritoneal cavity. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in physiological and pathological angiogenesis, and elevated levels of VEGF are found in peritoneal fluid of patients with endometriosis. Our aim was to investigate the site of expression and regulation of VEGF in endometriosis. VEGF immunoreactivity was found in tissue macrophages present in ectopic endometrium and in activated peritoneal fluid macrophages. Macrophage activation was highest in women with endometriosis, and media conditioned by peritoneal fluid macrophages from these women caused a VEGF-dependent increase in endothelial cell proliferation above that seen from normal women. Peritoneal fluid macrophages secreted VEGF in response to ovarian steroids, and this secretion was enhanced after activation with lipopolysaccharide. Peritoneal fluid macrophages expressed receptors for steroid hormones. VEGF receptors flt and KDR (kinase domain receptor) were also detected, suggesting autocrine regulation. During the menstrual cycle, expression of flt was constant but that of KDR was increased in the luteal phase, at which time the cells migrated in response to VEGF. KDR expression and the migratory response were significantly higher in patients with endometriosis. This study demonstrates that activated macrophages are a major source of VEGF in endometriosis and that this expression is regulated directly by ovarian steroids.

BACKGROUND: Two thirds of patients with ovarian carcinoma have advanced disease at diagnosis and have poor prognoses because of the presence of highly invasive carcinoma cells and rapidly accumulating ascitic fluid. Vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells, is produced in elevated amounts by many tumors, including ovarian carcinomas. The known human receptors for VEGF, flt and KDR, are both cell surface tyrosine kinases and are expressed predominantly on endothelial cells. Acting through these receptors, VEGF may stimulate angiogenesis and promote tumor progression. PURPOSE: We aimed to clarify the function of VEGF in tumor development by identifying the cells in ovarian carcinoma tissue that express VEGF and its receptors. METHODS: VEGF, flt, and KDR expression was localized by in situ hybridization and immunohistochemistry in frozen sections of primary tumors from five patients with ovarian carcinoma and from metastases of ovarian carcinoma from three different patients. Reverse transcription followed by polymerase chain reaction (RT-PCR) and an enzyme-linked immunosorbent assay were used to analyze VEGF, flt, and KDR expression in six epithelial cell lines derived from ovarian carcinoma ascites from five additional patients. RESULTS: Messenger RNAs (mRNAs) encoding VEGF, flt, and KDR were detected in primary ascitic cells and in three of four ovarian carcinoma cell lines examined by RT-PCR. Two novel complementary DNAs that may encode truncated, soluble forms of flt were cloned from one primary source. VEGF levels of 20-120 pM were found in culture media conditioned by the cell lines. Elevated expression of VEGF mRNA was found in all primary tumors and metastases, especially at the margins of tumor acini. VEGF immunoreactivity was concentrated in clusters of tumor cells and patches of stromal matrix. flt immunoreactivity was confined to tumor blood vessels, but flt mRNA was not detected by in situ hybridization. In contrast, KDR mRNA was detected not only in vascular endothelial cells but also in tumor cells at primary malignant sites. CONCLUSIONS: VEGF is expressed by tumor cells in primary and metastatic ovarian carcinoma and accumulates in the stromal matrix. Its receptors, flt and KDR, are expressed by some tumor cells that coexpress VEGF. This is the first localization of KDR expression in nonendothelial cells. IMPLICATIONS: Coexpression of VEGF and KDR by tumor cells in ovarian carcinoma raises the possibility of autocrine stimulation and of therapeutic strategies targeting this receptor-ligand interaction.

Studies of amniotic testosterone in humans suggest that fetal testosterone (fT) is related to specific (but not all) sexually dimorphic aspects of cognition and behaviour. It has also been suggested that autism may be an extreme manifestation of some male-typical traits, both in terms of cognition and neuroanatomy. In this paper, we examine the possibility of a link between autistic traits and fT levels measured in amniotic fluid during routine amniocentesis. Two instruments measuring number of autistic traits (the Childhood Autism Spectrum Test (CAST) and the Child Autism Spectrum Quotient (AQ-Child)) were completed by these women about their children (N=235), ages 6-10 years. Intelligence Quotient (IQ) was measured in a subset of these children (N=74). fT levels were positively associated with higher scores on the CAST and AQ-Child. This relationship was seen within sex as well as when the sexes were combined, suggesting this is an effect of fT rather than of sex per se. No relationships were found between overall IQ and the predictor variables, or between IQ and CAST or AQ-Child. These findings are consistent with the hypothesis that prenatal androgen exposure is related to children exhibiting more autistic traits. These results need to be followed up in a much larger sample to test if clinical cases of ASC have elevated fT.

Repair of human endometrium after menstruation and preparation of the endometrium for implantation involves profound angiogenic changes. Vascular endothelial cell growth factor (VEGF) is a recently identified growth factor with significant angiogenic properties. Four species of mRNA encoding VEGFs were identified in human endometrium and myometrium. All species were present throughout the menstrual cycle. Two species, VEGF165 and VEGF121, were present in peripheral leukocytes, indicating tissue-specific splicing of the two other VEGF transcripts. In situ hybridization of mRNA encoding VEGF was not restricted to vascular smooth muscle but was present in epithelial and stromal cells of endometrium throughout the cycle, and the distribution changed during the course of the cycle. All four species of VEGF were expressed by the endometrial carcinoma cell lines Ishikawa, HEC 1-A, and HEC 1-B. Estradiol increased steady-state levels of mRNA encoding VEGF in a dose- and time-dependent manner in HEC 1-A cells. Conditioned medium from these cells possessed angiogenic activity that was depleted by passage through a heparin affinity column. None of the cell lines demonstrated mRNA for acidic or basic fibroblast growth factor (FGF), despite previous reports of the identification of immunoreactive basic FGF in HEC 1-A and HEC 1-B cells. These findings show that VEGFs, not FGFs, are the principal angiogenic growth factors secreted by these cells and that human endometrium expresses a secreted angiogenic growth factor whose site of expression changes during the menstrual cycle.

BACKGROUND: Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation. METHODS AND FINDINGS: We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37-39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12-1.20; 33-36 wk adjusted OR 1.53, 95% CI 1.43-1.63; 28-32 wk adjusted OR 2.66, 95% CI 2.38-2.97; 24-27 wk adjusted OR 6.92, 95% CI 5.58-8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37-39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases. CONCLUSIONS: Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery.

OBJECTIVE: To investigate the incidence of spontaneous abortion in a population of women in order to establish their risk of spontaneous abortion and the obstetric factors predisposing to it. DESIGN: Prospective study of women recruited by radio and poster appeal and from hospital outpatient clinics. SETTING: English provincial community. PATIENTS: 630 Women from the general population intending to become pregnant. INTERVENTIONS: The viability of the pregnancy was assessed by abdominal ultrasonography before completion of the eighth week, and the assessment was repeated if vaginal bleeding occurred. MAIN OUTCOME MEASURE: Spontaneous abortion or live births in women with or without a previous history of spontaneous abortion. RESULTS: The overall incidence of clinically recognisable spontaneous abortion before 20 weeks of gestation was 12% (50/407 pregnancies). The risk of spontaneous abortion in each category of patient was classified with respect to the patient's past reproductive performance and found to be influenced greatly by her previous obstetric history. In primigravidas and women with a history of consistently successful pregnancies the incidences of abortion were low (5% (4/87) and 4% (3/73) respectively), whereas women with only unsuccessful histories had a much greater risk of aborting the study pregnancy (24% (24/98)), even when their sole pregnancy had ended in abortion (20% (12/59)). The outcome of the last pregnancy also influenced the outcome of the study pregnancy; only 5% of women (5/95) whose previous pregnancy had been successful aborted, whereas the incidence of loss of pregnancy among women whose last pregnancy had aborted was 19% (40/214). CONCLUSIONS: A knowledge of the patient's reproductive history is essential for the clinical assessment of her risk of spontaneous abortion. As the most important predictive factor for spontaneous abortion is a previous abortion, the outcome of a woman's first pregnancy has profound consequences for all subsequent pregnancies.

Vascular endothelial growth factor (VEGF) is a potent secreted factor that promotes angiogenesis and maintains the integrity of the endothelium. Levels of VEGF are increased in many tumors and are elevated in women with pre-eclampsia, a serious disease of pregnancy. Here we show by in situ hybridization that the trophoblast contains the mRNA encoding a soluble version of the VEGF receptor known as Flt-1 (sFlt-1: initially described by Kendall and Thomas, PNAS 90:10705-10709). Binding assays and Western blotting of villus-conditioned media confirmed the production of sFlt-1. Serum from pregnant women was found to contain a VEGF-binding protein that was not present in serum from men or nonpregnant women. As determined by heparin affinity, column fractionation, and cross-linking, this protein was identical to sFlt-1. Taken together, these results show that the placenta secretes sFlt-1, which would be expected to be a VEGF antagonist. This is the first report of production of the sFlt-1 receptor in vivo, and it reveals a new mechanism for naturally regulating this potent angiogenic agent. The presence of such an antagonist suggests that regulation of VEGF action is essential to successful pregnancy. This has important implications for the activity of VEGF locally and systemically in other conditions.

The C statistic is a commonly reported measure of screening test performance. Optimistic estimation of the C statistic is a frequent problem because of overfitting of statistical models in small data sets, and methods exist to correct for this issue. However, many studies do not use such methods, and those that do correct for optimism use diverse methods, some of which are known to be biased. We used clinical data sets (United Kingdom Down syndrome screening data from Glasgow (1991-2003), Edinburgh (1999-2003), and Cambridge (1990-2006), as well as Scottish national pregnancy discharge data (2004-2007)) to evaluate different approaches to adjustment for optimism. We found that sample splitting, cross-validation without replication, and leave-1-out cross-validation produced optimism-adjusted estimates of the C statistic that were biased and/or associated with greater absolute error than other available methods. Cross-validation with replication, bootstrapping, and a new method (leave-pair-out cross-validation) all generated unbiased optimism-adjusted estimates of the C statistic and had similar absolute errors in the clinical data set. Larger simulation studies confirmed that all 3 methods performed similarly with 10 or more events per variable, or when the C statistic was 0.9 or greater. However, with lower events per variable or lower C statistics, bootstrapping tended to be optimistic but with lower absolute and mean squared errors than both methods of cross-validation.

Active endometriosis is characterized by hypervascularization both within and surrounding the implant; therefore the presence of angiogenic factors in the peritoneal environment would be of great importance. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in both physiological and pathological angiogenesis. We sought to determine if VEGF was present in the peritoneal fluid of women with and without endometriosis, and to establish if differences exist between these groups. VEGF was present in all patients sampled. The fluid from patients with endometriosis contained significantly greater amounts of VEGF than controls. Cyclic variations in VEGF concentration were seen in fluid from patients with endometriosis, the VEGF concentration in proliferative phase being significantly higher than in the secretory phase. The concentration of VEGF in this fluid was also significantly higher than that found in the proliferative and secretory phases of women without endometriosis. No cyclic variations in VEGF were seen in the control group. We suggest that elevated levels of VEGF in the peritoneal fluid of patients with endometriosis may be critical in the pathogenesis of endometriosis.

CONTEXT: Trial of labor after previous cesarean delivery is associated with increased risk of uterine rupture. However, no reliable data exist on the effect of a trial of labor on the risk of perinatal death in otherwise uncomplicated term pregnancies. OBJECTIVE: To determine the risk of intrapartum stillbirth or neonatal death not related to congenital abnormality among women with uncomplicated term pregnancies who had a trial of labor after previous cesarean delivery, compared with women having a planned repeat cesarean delivery, and multiparous and nulliparous women at term not delivered by planned cesarean method. DESIGN AND SETTING: Population-based, retrospective cohort study of data from the linked Scottish Morbidity Record and Stillbirth and Neonatal Death Enquiry encompassing births in Scotland between January 1, 1992, and December 31, 1997. POPULATION: A total of 313 238 singleton births between 37 and 43 weeks' gestational age in which the fetus was in a cephalic presentation. MAIN OUTCOME MEASURE: Delivery-related perinatal death, defined as intrapartum stillbirth or neonatal death unrelated to congenital anomaly, compared among the 4 groups. RESULTS: Among women who had a trial of labor following previous cesarean delivery (n = 15 515), the overall rate of delivery-related perinatal death was 12.9 (95% confidence interval [CI], 7.9-19.9) per 10 000 women. This was approximately 11 times greater (odds ratio [OR], 11.6; 95% CI, 1.6-86.7) than the risk associated with planned repeat cesarean delivery (n = 9014), more than twice (OR, 2.2; 95% CI, 1.3-3.5) the risk associated with other multiparous women in labor (n = 151 549), and similar to the risk among nulliparous women in labor (n = 137 160; OR, 1.3; 95% CI, 0.8-2.1). The associations were not explained by differences in maternal height, smoking status, socioeconomic status, age, fetal growth, or week of gestation at delivery. Among women having a trial of labor, the rate of death due to mechanical causes, including uterine rupture, was 4.5 (95% CI, 1.8-9.3) per 10 000 women. This was more than 8 times greater than other multiparous women (OR, 8.5; 95% CI, 3.2-22.3) and nulliparous women (OR, 8.8; 95% CI, 3.2-24.2). CONCLUSIONS: The absolute risk of perinatal death associated with trial of labor following previous cesarean delivery is low. However, in our study, the risk was significantly higher than that associated with planned repeat cesarean delivery, and there was a marked excess of deaths due to uterine rupture compared with other women in labor.

OBJECTIVE: To determine whether a short interval between pregnancies is an independent risk factor for adverse obstetric outcome. DESIGN: Retrospective cohort study. SETTING: Scotland. SUBJECTS: 89 143 women having second births in 1992-8 who conceived within five years of their first birth. MAIN OUTCOME MEASURES: Intrauterine growth restriction (birth weight less than the 5th centile for gestational age), extremely preterm birth (24-32 weeks), moderately preterm birth (33-36 weeks), and perinatal death. RESULTS: Women whose subsequent interpregnancy interval was less than six months were more likely than other women to have had a first birth complicated by intrauterine growth restriction (odds ratio 1.3, 95% confidence interval 1.1 to 1.5), extremely preterm birth (4.1, 3.2 to 5.3), moderately preterm birth (1.5, 1.3 to 1.7), or perinatal death (24.4, 18.9 to 31.5). They were also shorter, less likely to be married, and more likely to be aged less than 20 years at the time of the second birth, to smoke, and to live in an area of high socioeconomic deprivation. When the outcome of the second birth was analysed in relation to the preceding interpregnancy interval and the analysis confined to women whose first birth was a term live birth (n = 69 055), no significant association occurred (adjusted for age, marital status, height, socioeconomic deprivation, smoking, previous birth weight vigesimal, and previous caesarean delivery) between interpregnancy interval and intrauterine growth restriction or stillbirth. However, a short interpregnancy interval (< 6 months) was an independent risk factor for extremely preterm birth (adjusted odds ratio 2.2, 1.3 to 3.6), moderately preterm birth (1.6, 1.3 to 2.0), and neonatal death unrelated to congenital abnormality (3.6, 1.2 to 10.7). The adjusted attributable fractions for these associations were 6.1%, 3.9%, and 13.8%. The associations were very similar when the analysis was confined to married non-smokers aged 25 and above. CONCLUSIONS: A short interpregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth.

The theory of developmental programming suggests that diseases such as the metabolic syndrome may be 'programmed' by exposure to adverse stimuli during early development. The developmental programming literature encompasses the study of a wide range of suboptimal intrauterine environments in a variety of species and correlates these with diverse phenotypic outcomes in the offspring. At a molecular level, a large number of variables have been measured and suggested as the basis of the programmed phenotype. The range of both dependent and independent variables studied often makes the developmental programming literature complex to interpret and the drawing of definitive conclusions difficult. A common, though under-explored, theme of many developmental programming models is a sex difference in offspring outcomes. This holds true across a range of interventions, including dietary, hypoxic, and surgical models. The molecular and phenotypic outcomes of adverse in utero conditions are often more prominent in male than female offspring, although there is little consideration given to the basis for this observation in most studies. We review the evidence that maternal energy investment in male and female conceptuses may not be equal and may be environment dependent. It is suggested that male and female development could be viewed as separate processes from the time of conception, with differences in both timing and outcomes.

PURPOSE: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. METHODS: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. RESULTS: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9-27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6-16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score < 19, ICU stay > 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2-1.8), stage II (OR 1.6; 95% CI 1.4-1.9), and stage III or worse (OR 2.8; 95% CI 2.3-3.3). CONCLUSION: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat.

Mammals, including humans, show sex differences in juvenile play behavior. In rodents and nonhuman primates, these behavioral sex differences result, in part, from sex differences in androgens during early development. Girls exposed to high levels of androgen prenatally, because of the genetic disorder congenital adrenal hyperplasia, show increased male-typical play, suggesting similar hormonal influences on human development, at least in females. Here, we report that fetal testosterone measured from amniotic fluid relates positively to male-typical scores on a standardized questionnaire measure of sex-typical play in both boys and girls. These results show, for the first time, a link between fetal testosterone and the development of sex-typical play in children from the general population, and are the first data linking high levels of prenatal testosterone to increased male-typical play behavior in boys.

OBJECTIVE: To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. DESIGN: Phase II randomised, single blinded, parallel clinical trial. SETTING: Eight tertiary neonatal intensive care units in eight European countries. PARTICIPANTS: 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. INTERVENTIONS: Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). MAIN OUTCOME MEASURES: The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. RANDOMISATION: Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥ 26 weeks). BLINDING: Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. RESULTS: The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. CONCLUSIONS: Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring.Trial registration ClinicalTrial.gov NCT01590316.

A large multicentre study on the short and long term clinical and developmental outcome of infants randomised to different diets is being undertaken. This report represents an interim analysis of the early postnatal growth performance of an unselected population of 194 preterm infants (gestation, mean (SD) 31 . 0 (2 . 9) weeks; birthweight, mean (SD) 1364 (294) g), both ill and well, examined in two (of four) parallel trials. One trial compared banked breast milk with a new preterm formula (primary trial); the other compared these diets as supplements to maternal milk (supplement trial). A major dietary effect on the number of days taken to regain birthweight and subsequent gains in weight, length, and head circumference was observed in the primary trial. Infants fed banked breast milk and weighing less than 1200 g at birth took a calculated additional three weeks to reach 2000 g compared with those fed on the preterm formula. A significant influence of diet on body proportions was seen in the relation between body weight, head circumference, and length. Similar though smaller differences in growth patterns were seen in the supplement trial. By the time they reach 2000 g, infants of birthweights 1200 to 1849 g fed on banked breast milk and infants below 1200 g fed on either banked breast milk or maternal milk supplemented (as necessary) with banked breast milk, fulfilled stringent criteria for failure to thrive (weight less than 2 SD below the mean for age). Only infants fed the preterm formula as their sole diet had maintained their birth centile by discharge from hospital. The misleading nature of comparisons between extrauterine and intrauterine steady state weight gains is emphasised.