Maternal pre-pregnancy body mass index and risk of preterm birth: a collaboration using large routine health datasets.

BACKGROUND: Preterm birth (PTB) is a leading cause of child morbidity and mortality. Evidence suggests an increased risk with both maternal underweight and obesity, with some studies suggesting underweight might be a greater factor in spontaneous PTB (SPTB) and that the relationship might vary by parity. Previous studies have largely explored established body mass index (BMI) categories. Our aim was to compare associations of maternal pre-pregnancy BMI with any PTB, SPTB and medically indicated PTB (MPTB) among nulliparous and parous women across populations with differing characteristics, and to identify the optimal BMI with lowest risk for these outcomes. METHODS: We used three UK datasets, two USA datasets and one each from South Australia, Norway and Denmark, together including just under 29 million pregnancies resulting in a live birth or stillbirth after 24 completed weeks gestation. Fractional polynomial multivariable logistic regression was used to examine the relationship of maternal BMI with any PTB, SPTB and MPTB, among nulliparous and parous women separately. The results were combined using a random effects meta-analysis. The estimated BMI at which risk was lowest was calculated via differentiation and a 95% confidence interval (CI) obtained using bootstrapping. RESULTS: We found non-linear associations between BMI and all three outcomes, across all datasets. The adjusted risk of any PTB and MPTB was elevated at both low and high BMIs, whereas the risk of SPTB was increased at lower levels of BMI but remained low or increased only slightly with higher BMI. In the meta-analysed data, the lowest risk of any PTB was at a BMI of 22.5 kg/m2 (95% CI 21.5, 23.5) among nulliparous women and 25.9 kg/m2 (95% CI 24.1, 31.7) among multiparous women, with values of 20.4 kg/m2 (20.0, 21.1) and 22.2 kg/m2 (21.1, 24.3), respectively, for MPTB; for SPTB, the risk remained roughly largely constant above a BMI of around 25-30 kg/m2 regardless of parity. CONCLUSIONS: Consistency of findings across different populations, despite differences between them in terms of the time period covered, the BMI distribution, missing data and control for key confounders, suggests that severe under- and overweight may play a role in PTB risk.

Acoustic tethering of microorganisms.

We show how to construct and apply a setup to acoustically tether and enable behavioral observations of individual microorganisms using simple laboratory equipment and a standard light microscope. We explore the capability of the setup with the freely swimming dinoflagellate Alexandrium minutum as the study organism. The setup allows us to tether cells in focus in the mid-plane of the sample chamber and make observations of individual organisms at high magnification without affecting their flagellar beat frequencies. We discuss the prospect of the method to explore appendage motion and swimming kinematics of other flagellates and ciliates, and we argue that the method will be applicable to a broad range of cell sizes and shapes.

Pregnancy and risk of COVID-19: a Norwegian registry-linkage study.

OBJECTIVE: To compare the risk of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and contact with specialist healthcare services for coronavirus disease 2019 (COVID-19) between pregnant and non-pregnant women. POPULATION OR SAMPLE: All women ages 15-45 living in Norway on 1 March 2020 (n = 1 033 699). METHODS: We linked information from the national birth, patient, communicable diseases and education databases using unique national identifiers. MAIN OUTCOME MEASURE: We estimated hazard ratios (HR) among pregnant compared to non-pregnant women of having a positive test for SARS-CoV-2, a diagnosis of COVID-19 in specialist healthcare, or hospitalisation with COVID-19 using Cox regression. Multivariable analyses adjusted for age, marital status, education, income, country of birth and underlying medical conditions. RESULTS: Pregnant women were not more likely to be tested for or to a have a positive SARS-CoV-2 test (adjusted HR 0.99; 95% CI 0.92-1.07). Pregnant women had higher risk of hospitalisation with COVID-19 (HR 4.70, 95% CI 3.51-6.30) and any type of specialist care for COVID-19 (HR 3.46, 95% CI 2.89-4.14). Pregnant women born outside Scandinavia were less likely to be tested, and at higher risk of a positive test (HR 2.37, 95% CI 2.51-8.87). Compared with pregnant Scandinavian-born women, pregnant women with minority background had a higher risk of hospitalisation with COVID-19 (HR 4.72, 95% CI 2.51-8.87). CONCLUSION: Pregnant women were not more likely to be infected with SARS-CoV-2. Still, pregnant women with COVID-19, especially those born outside of Scandinavia, were more likely to be hospitalised. TWEETABLE ABSTRACT: Pregnant women are at increased risk of hospitalisation for COVID-19.

Experiences of grief-bereavement after a medically assisted death in Canada: Bringing death to life.

Medical assistance in dying (MAiD) legislation was passed in Canada in 2016, yet the bereavement experience of family and friends is not well understood. Using interpretive description, we interviewed nine bereaved individuals. The time before the assisted death seems most impactful-an experience of bringing death to life shapes bereavement after death. We identified themes that inform this grieving: (1) certainty of date/time of death-intensifies a parade of lasts, initiates a countdown and affords time to say good-bye; (2) active family engagement as planners supports sense-making; and (3) enacting MAiD as ceremony slows time to "digest" loss.

Follicular hormone dynamics during the midcycle surge of gonadotropins in women undergoing fertility treatment.

Changes in concentrations of intra-follicular hormones during ovulation are important for final oocyte maturation and endometrial priming to ensure reproductive success. As no human studies have investigated these changes in detail, our objective was to describe the dynamics of major follicular fluid (FF) hormones and transcription of steroidogenic enzymes and steroid receptors in human granulosa cells (GCs) during ovulation. We conducted a prospective cohort study at a public fertility clinic in 2016-2018. Fifty women undergoing ovarian stimulation for fertility treatment were included. From each woman, FF and GCs were collected by transvaginal ultrasound-guided follicle puncture of one follicle at two specific time points during ovulation, and the study covered a total of five time points: before ovulation induction (OI), 12, 17, 32 and 36 h after OI. Follicular fluid concentrations of oestradiol, progesterone, androstenedione, testosterone, 17-hydroxyprogesterone, anti-Mullerian hormone, inhibin A and inhibin B were measured using ELISA assays, and a statistical mixed model was used to analyse differences in hormone levels between time points. Gene expression of 33 steroidogenic enzymes and six hormone receptors in GCs across ovulation were assessed by microarray analysis, and selected genes were validated by quantitative reverse transcription PCR. We found that concentrations of oestradiol, testosterone, progesterone, AMH, inhibin A and inhibin B (P < 0.001) and gene expression of 12 steroidogenic enzymes and five receptors (false discovery rate < 0.0001) changed significantly during ovulation. Furthermore, we found parallel changes in plasma hormones. The substantial changes in follicular hormone production during ovulation highlight their importance for reproductive success.

20 years of the European IVF-monitoring Consortium registry: what have we learned? A comparison with registries from two other regions.

STUDY QUESTION: How has the performance of the European regional register of the European IVF-monitoring Consortium (EIM)/European Society of Human Reproduction and Embryology (ESHRE) evolved from 1997 to 2016, as compared to the register of the Centres for Disease Control and Prevention (CDC) of the USA and the Australia and New Zealand Assisted Reproduction Database (ANZARD)? SUMMARY ANSWER: It was found that coherent and analogous changes are recorded in the three regional registers over time, with a different intensity and pace, that new technologies are taken up with considerable delay and that incidental complications and adverse events are only recorded sporadically. WHAT IS KNOWN ALREADY: European data on ART have been collected since 1997 by EIM. Data collection on ART in Europe is particularly difficult due to its fragmented political and legal landscape. In 1997, approximately 78.1% of all known institutions offering ART services in 23 European countries submitted data and in 2016 this number rose to 91.8% in 40 countries. STUDY DESIGN, SIZE, DURATION: We compared the changes in European ART data as published in the EIM reports (2001-2020) with those of the USA, as published by CDC, and with those of Australia and New Zealand, as published by ANZARD. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a retrospective analysis of the published EIM data sets spanning the 20 years observance period from 1997 to 2016, together with the published data sets of the USA as well as of Australia and New Zealand. By comparing the data sets in these three large registers, we analysed differences in the completeness of the recordings together with differences in the time intervals on the occurrence of important trends in each of them. Effects of suspected over- and under-reporting were also compared between the three registers. X2 log-rank analysis was used to assess differences in the data sets. MAIN RESULTS AND THE ROLE OF CHANCE: During the period 1997-2016, the numbers of recorded ART treatments increased considerably (5.3-fold in Europe, 4.6-fold in the USA, 3.0-fold in Australia and New Zealand), while the number of registered treatment modalities rose from 3 to 7 in Europe, from 4 to 10 in the USA and from 5 to 8 in Australia and New Zealand, as published by EIM, CDC and ANZARD, respectively. The uptake of new treatment modalities over time has been very different in the three registers. There is a considerable degree of underreporting of the number of initiated treatment cycles in Europe. The relationship between IVF and ICSI and between fresh and thawing cycles evolved similarly in the three geographical areas. The freeze-all strategy is increasingly being adopted by all areas, but in Europe with much delay. Fewer cycles with the transfer of two or more embryos were reported in all three geographical areas. The delivery rate per embryo transfer in thawing cycles bypassed that in fresh cycles in the USA in 2012, in Australia and New Zealand in 2013, but not yet in Europe. As a result of these changing approaches, fewer multiple deliveries have been reported. Since 2012, the most documented adverse event of ART in all three registers has been premature birth (<37 weeks). Some adverse events, such as maternal death, ovarian hyperstimulation syndrome, haemorrhage and infections, were only recorded by EIM and ANZARD. LIMITATIONS, REASONS FOR CAUTION: The methods of data collection and reporting were very different among European countries, but also among the three registers. The better the legal background on ART surveillance, the more complete are the data sets. Until the legal obligation to report is installed in all European countries together with an appropriate quality control of the submitted data the reported numbers and incidences should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The growing number of reported treatments in ART, the higher variability in treatment modalities and the rising contribution to the birth rates over the last 20 years point towards the increasing impact of ART. High levels of completeness in data reporting have been reached, but inconsistencies and inaccuracies still remain and need to be identified and quantified. The current trend towards a higher diversity in treatment modalities and the rising impact of cryostorage, resulting in improved safety during and after ART treatment, require changes in the organization of surveillance in ART. The present comparison must stimulate all stakeholders in ART to optimize surveillance and data quality assurance in ART. STUDY FUNDING/COMPETING INTEREST(S): This study has no external funding and all costs are covered by ESHRE. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Clinical characteristics including cardiovascular and metabolic risk factors in adolescents with psoriasis.

BACKGROUND: Clinical studies on psoriasis in adolescents have mainly been performed in patients with severe psoriasis. Population-based studies of clinical characteristics and risk factors for later cardiovascular and metabolic disease in children and adolescents are lacking. OBJECTIVES: To examine the clinical characteristics of adolescents with psoriasis nested in a general population cohort. Furthermore, to investigate cardiovascular and metabolic risk factors in the adolescents with psoriasis compared to parentally predisposed and non-predisposed adolescents without psoriasis from the same birth cohort. METHODS: We identified adolescents with and without psoriasis using a nationwide general population birth cohort in Denmark. A clinical examination included skin inspection and scoring of psoriasis severity, completion of a questionnaire on psoriasis and comorbidities, physical measurements, and blood sampling. Participants also completed self-administered questionnaires on quality of life and mental health. RESULTS: We included 81 adolescents with psoriasis and 234 controls (110 with genetic predisposition for psoriasis and 124 without predisposition). Median age was 15.6 (13.5-18.5) years, and in those with active psoriasis, median Psoriasis Area and Severity Index score was 1.2 (0.1-11.4). The scalp was the most common site of psoriasis, both at debut and at time of examination. Diaper rash in infancy was more frequent in the psoriasis group. No significant differences regarding quality of life, anxiety and depression were found. More adolescents with psoriasis were obese (8.6% vs. 1.7%, P = 0.008), and physical measures of abdominal obesity were also significantly higher. HbA1c was significantly higher (31.55 vs. 30.81 mmol/mol, P = 0.048), while no differences were found for blood pressure, lipids or high-sensitivity C-reactive protein. In a subgroup analysis, this was evident in the non-predisposed psoriasis-free controls only. CONCLUSIONS: Overall, adolescents with psoriasis from this general population had mild disease. Still, early markers of cardiovascular and metabolic disease were elevated.

Early BCG Vaccination, Hospitalizations, and Hospital Deaths: Analysis of a Secondary Outcome in 3 Randomized Trials from Guinea-Bissau.

Background: This study was performed to examine the effects of early BCG vaccination on the risk, cause, and severity of infant hospitalizations. The analysis included 3 trials randomizing low-weight neonates to early BCG vaccination (intervention) versus no BCG vaccination (usual practice in low-weight neonates, control), with hospitalizations as secondary outcome. Methods: Hospitalization data were collected at the pediatric ward of the National Hospital. Effects of BCG vaccination on hospitalization risk were assessed in Cox models providing overall and major disease-group incidence rate ratios (IRRs). Severity was assessed by means of in-hospital case-fatality rates and compared by group as cohort study risk ratios (RRs). Results: Among 6583 infants (3297 in BCG group, 3286 controls), there were 908 infant hospitalizations (450 BCG, 458 controls) and 135 in-hospital deaths (56 BCG, 79 controls). The neonatal (28 days), 6-week, and infant (1-year) BCG versus control hospitalization IRRs were 0.97 (95% confidence interval [CI], .72-1.31), 0.95 (.73-1.24), and 0.96 (.84-1.10). Corresponding BCG versus control case-fatality rate RRs were 0.58 (95% CI, .35-.94), 0.56 (.35-.90), and 0.72 (.53-.99). BCG vaccination tended to reduce neonatal and infant sepsis hospitalization rates (IRR, 0.75 [95% CI, .50-1.13] and 0.78 [.55-1.11], respectively), and it reduced the neonatal in-hospital sepsis mortality rate (RR, 0.46; 95% CI, .22-.98). There were no confirmed hospitalizations for tuberculosis. Conclusions: BCG vaccination did not affect hospitalization rates but reduced in-hospital mortality rates significantly, primarily by preventing fatal cases of sepsis. The observed beneficial effects of BCG on the in-hospital mortality rate were entirely nonspecific. Clinical Trials Registration: NCT00146302, NCT00168610, and NCT00625482.

Cumulative live birth rate prognosis based on the number of aspirated oocytes in previous ART cycles.

STUDY QUESTION: Is the number of aspirated oocytes in the first ART cycle associated with the cumulative live birthrates (CLBR) in subsequent cycles? SUMMARY ANSWER: The number of aspirated oocytes in the first cycle was associated with CLBR in subsequent cycles. Previous treatment response predicts outcome in future cycles. WHAT IS KNOWN ALREADY: Previous reports have shown a positive association between the number of retrieved oocytes and live birthrate per fresh treatment cycle. This has also been shown for the CLBR in one complete ART-cycle, including possible subsequent frozen-thawed transfers (FER). It has been shown that women with less than five oocytes in the first cycle have poorer outcome within six complete cycles than women with more than 12 oocytes, suggesting that the number of aspirated oocytes in the first cycle may be reproduced in later cycles. However, other studies have shown that an initial low treatment response may be improved with increased gonadotrophin start-dose. STUDY DESIGN, SIZE, DURATION: The Danish National IVF-registry includes all ART treatments in public and private clinics since 1994. Treatment-cycles were cross-linked with the Medical Birth Registry, identifying treatment-related births and natural conception births. This national cohort study includes all women starting ART treatments with homologous eggs between 2002 and 2011, N = 30 486. Subjects were followed for up to four fresh ART-cycles including subsequent FER-cycles (=four complete cycles), until the first livebirth, or until December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: The CLBR within 1-4 complete ART-cycles were calculated as the proportion of women with a livebirth, out of all women initiating ART-treatment, including drop-outs (no livebirth or no continued treatment within follow-up). In women with one year follow-up from last treatment, multivariate logistic regression analysis assessed impact of retrieved oocytes on CLBR, adjusting results for female age and cause of infertility. Hospital admission due to ovarian hyperstimulation syndrome (OHSS) was reported. MAIN RESULTS AND THE ROLE OF CHANCE: After one, two and three complete ART-cycles, the CLBRs attributable to ART treatment were 26.4% [95%CI 25.9-26.9], 42.6% [42.0-43.1] and 51.3% [50.7-51.9], respectively. The CLBR attributable to non-ART related conception (natural conception or intrauterine insemination) were 5.3% [5.0-5.6], 8.3% [8.0-8.7] and 10.6% [10.3-11.0], after one, two and three complete cycles. In women without a live birth in the first complete cycle, the number of aspirated oocytes predicted the outcome in the second and third cycle: When compared to women with 0-3 aspirated oocytes in the first cycle, the odds for live birth in the second and third cycle was 1.18 [1.07-1.30] for women with 4-9 aspirated oocytes in the first cycle, 1.41 [1.27-1.57] for women with 10-15 aspirated oocytes and 1.63 [1.42-1.88] for women with more than 15 aspirated oocytes. For women without a livebirth in the first and second cycle, the sum of aspirated oocytes predicted outcome in the third complete cycle. Women with a sum larger than six aspirated oocytes, had marked increased odds ratios for livebirth in the third complete cycle, compared to women with a sum of 0-6 oocytes in the first and second fresh cycle. Incidence of hospital-admission due to OHSS was 1.7% in the first cycle, decreasing to 1.3% and 1.0% in the second and third cycles. LIMITATIONS, REASONS FOR CAUTION: Although mandatory, there may be treatment-cycles not registered in the IVF-registry. Missing information in number of aspirated oocytes are most likely random losses of information. There were few observations in women with more than 15 aspirated oocytes and these birthrates should be interpreted cautiously. Information on gonadotrophin dose used for stimulation was not available, nor was information on dose adjustments in subsequent cycles. WIDER IMPLICATIONS OF THE FINDINGS: With these results we can counsel couples returning for fertility treatments, providing an age-stratified revised prognosis for chances of live birth and risk of OHSS, reflecting prior failed attempts and previous ovarian response. STUDY FUNDING/COMPETING INTEREST(S): This study was unconditionally funded by Ferring Pharmaceuticals and ReproUnion. The funders had no role in the study design, data collection and interpretation, or decision to submit the work for publication. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (J.nr. 2012-41-1330).

Prediction of the lower serum anti-Müllerian hormone threshold for ovarian stimulation prior to in-vitro fertilization using the Elecsys® AMH assay: a prospective observational study.

BACKGROUND: In assisted reproductive technology, prediction of treatment failure remains a great challenge. The development of more sensitive assays for measuring anti-Müllerian hormone (AMH) has allowed for the possibility to investigate if a lower threshold of AMH can be established predicting very limited or no response to maximal ovarian stimulation. METHODS: A prospective observational multicenter study of 107 women, < 40 years of age with regular menstrual cycle and serum AMH levels ≤ 12 pmol/L, treated with 300 IU/day of HP-hMG in a GnRH-antagonist protocol. AMH was measured before treatment start using the Elecsys® AMH assay by Roche Diagnostics. The ability of AMH to predict follicular development and ovarian response was assessed by receiver operating characteristics (ROC). Furthermore, the relationship between AMH at start of stimulation and cycle outcome was investigated using multivariate logistic regression analysis. RESULTS: Five out of 107 cycles (4.7%) were cancelled due to lack of follicular development and 60/107 (56%) women did not reach the classical hCG criteria for ovulation induction (≥ 3 follicles of ≥17 mm). An AMH threshold of 4 pmol/L predicted failure to reach the classical hCG criteria with 89% specificity and 53% sensitivity and an area under the curve (AUC) of 0.76 (95% CI 0.66-0.85). AMH predicted cycle cancellation due to lack of follicular development, using a cut-off value of 1.5 pmol/L, with a specificity of 96% and sensitivity of 80% (AUC = 0.92, 95% CI 0.79-1.00). A single-unit increase in AMH was associated with a 29% decrease in odds of failure to reach the classical hCG criteria (OR 0.71 95% CI 0.59-0.85, p < 0.01). The lowest AMH value compatible with a live birth was 1.3 pmol/L. CONCLUSIONS: Among women with a limited ovarian reserve, pre-treatment serum AMH levels significantly predicted failure to reach the classical hCG triggering criteria and predicted lack of follicular development using a new sensitive assay, but AMH was not suitable for withholding fertility treatment, as even very low levels were associated with live births. TRIAL REGISTRATION: Not relevant.

Associations between maternal socioeconomic position and psoriasis: a cohort study among the offspring of the Danish National Birth Cohort.

BACKGROUND: The socioeconomic determinants of paediatric-onset psoriasis have not been previously investigated. OBJECTIVE: To identify whether a social gradient exists for paediatric-onset psoriasis, using measures of maternal socioeconomic position. METHODS: Data on paediatric-onset psoriasis from 36 003 Danish National Birth Cohort offspring were cross-linked with nationwide registry data on maternal age and three measures of maternal socioeconomic position: maternal educational attainment, maternal labour market attachment and equivalized household income. Univariable and multivariable logistic regression analyses were conducted to estimate the odds ratios (ORs) of psoriasis in the offspring, in cohort analyses for data from the year of enrolment and cross-sectional analyses from the year of the 11-year follow-up. RESULTS: Maternal age at birth, maternal educational attainment and equivalized household income were inversely associated with psoriasis in the offspring. Low maternal educational attainment was associated with offspring psoriasis [adjusted OR 1·62, 95% confidence interval (CI) 1·20-2·18] after adjusting for maternal psoriasis and age in the cohort analysis. The crude OR of psoriasis in offspring of mothers in the highest quartile compared with mothers in the lowest quartile of equivalized household income was 0·57 (95% CI 0·43-0·76), and the adjusted OR was 0·59 (95% CI 0·44-0·80) after adjusting for maternal psoriasis and age. Similar results were observed for data on maternal socioeconomic position at enrolment and at follow-up. CONCLUSIONS: A steep social gradient in paediatric-onset psoriasis was observed. Maternal socioeconomic position may play a role in early-life exposure to modifiable risk factors for psoriasis. Future studies may help to elucidate which biological factors mediate the social gradient observed in our study.

Structural brain maturation differs between preterm and term piglets, whereas brain activity does not.

AIM: The aim of the study was to investigate whether amplitude-integrated electroencephalography (aEEG) and cerebral magnetic resonance imaging (MRI) in preterm piglets would provide measures of cerebral functional, microstructural and anatomical maturation, which might reflect the signs of functional brain immaturity, documented in preterm piglets. METHODS: During July-October 2013 at the NEOMUNE Centre, Copenhagen University, Denmark, 31 preterm (90% gestation) and 10 term piglets underwent aEEG on days 1, 2, 4 and 11, and MRI on day 25. Physical activity levels were recorded. RESULTS: Preterm showed delayed neonatal arousal and physical activity, relative to term piglets. Preterm piglets had lower growth rates and brain volume than term piglets, but aEEG patterns were similar. MRI mean diffusivity was also similar, but fractional anisotropy (FA) was lower in preterm piglets (p < 0.001). CONCLUSION: Functional brain maturation, as assessed by aEEG, was relatively advanced in preterm piglets. Conversely, the low FA in the preterm piglets suggests that the white matter microstructure remains less mature in preterm compared to term piglets at postnatal day 25. The results might be utilised to define whether and how preterm piglets may contribute to preclinical models for brain development in preterm infants.

Prenatal risk factors influencing childhood BMI and overweight independent of birth weight and infancy BMI: a path analysis within the Danish National Birth Cohort.

BACKGROUND AND OBJECTIVES: Prenatal risk factors for childhood overweight may operate indirectly through development in body size in early life and/or directly independent hereof. We quantified the effects of maternal and paternal body mass index (BMI), maternal age, socioeconomic position (SEP), parity, gestational weight gain, maternal smoking during pregnancy, caesarean section, birth weight, and BMI at 5 and 12 months on BMI and overweight at 7 and 11 years. METHODS: Family triads with information on maternal, paternal and child BMI at ages 7 (n=29 374) and 11 years (n=18 044) were selected from the Danish National Birth Cohort. Information originated from maternal interviews and medical health examinations. Path analysis was used to estimate the direct and indirect effects of prenatal risk factors on childhood BMI z-scores (BMIz per unit score of the risk factor). Logistic regression was used to examine associations with overweight. RESULTS: The strongest direct effects on BMIz at age 7 were found for maternal and paternal BMI (0.19 BMIz and 0.14 BMIz per parental BMIz), low SEP (0.08 BMIz), maternal smoking (0.12 BMIz) and higher BMIz at 5 and 12 months (up to 0.19 BMIz per infant BMIz). For BMIz at age 11 with BMIz at age 7 included in the model, similar effects were found, but the direct effects of BMIz at age 5 and 12 months were mediated through BMI at age 7 (0.62 BMIz per BMIz). Same results were found for overweight. The sum of the direct effects can be translated to approximate absolute measures: 2.4 kg at 7 years, 5.7 kg at 11 years, in a child with average height and BMI. CONCLUSIONS: Parental BMI, low SEP and smoking during pregnancy have persisting, strong and direct effects on child BMI and overweight independent of birth weight and infancy BMI.

Fever and infections during pregnancy and psychosis-like experiences in the offspring at age 11. A prospective study within the Danish National Birth Cohort.

BACKGROUND: Maternal exposures to fever and infections in pregnancy have been linked to subsequent psychiatric morbidity in the child. This study examined whether fever and common infections in pregnancy were associated with psychosis-like experiences (PLEs) in the child. METHODS: A longitudinal study of 46 184 children who participated in the 11-year follow-up of the Danish National Birth Cohort was conducted. Pregnant women were enrolled between 1996 and 2002 and information on fever, genitourinary infections, respiratory tract infection, and influenza-like illness during pregnancy was prospectively collected in two interviews during pregnancy. PLEs were assessed using the seven-item Adolescent Psychotic-Like Symptom Screener in a web-based questionnaire completed by the children themselves at age 11. RESULTS: PLEs were reported among 11% of the children. Multinomial logistic regression models with probability weights to adjust for potential selection bias due to attrition suggested that maternal fever, genitourinary infections and influenza-like illness were associated with a weak to moderate increased risk of subclinical psychosis-like symptoms in the offspring, whereas respiratory tract infections were not. No clear pattern was observed between the strengths of the associations and the timing of exposure, or the type of psychosis-like symptom. CONCLUSIONS: In this study, maternal exposures to fevers and common infections in pregnancy were generally associated with a subtle excess risk of PLEs in the child. A more pronounced association was found for influenza-like illness under an a priori definition, leaving open the possibility that certain kinds of infections may constitute important risk factors.

Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1ß, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

The association between seasonal influenza-like illness cases and foetal death: a time series analysis.

It has been reported that foetal death follows a seasonal pattern. Influenza virus infection has been postulated as one possible contributor to this seasonal variation. This ecological study explored the temporal association between the influenza activity and the frequency of foetal death. Time series analysis was conducted using weekly influenza-like illness consultation proportions from the Danish sentinel surveillance system and weekly proportions of spontaneous abortions and stillbirths from hospital registers from 1994 to 2009. The association was examined in an autoregressive (AR) integrated (I) moving average (MA) model and subsequently analysed with cross-correlation functions. Our findings confirmed the well-known seasonality in influenza, but also seasonality in spontaneous abortion. No clear pattern of seasonality was found for stillbirths, although the analysis exposed dependency between observations. One final AR integrated MA model was identified for the influenza-like illness (ILI) series. We found no statistically significant relationship between weekly influenza-like illness consultation proportions and weekly spontaneous abortion proportions (five lags: P = 0.52; 11 lags: P = 0.91) or weekly stillbirths (five lags: P = 0.93; 11 lags: P = 0.40). Exposure to circulating influenza during pregnancy was not associated with rates of spontaneous abortions or stillbirths. Seasonal variations in spontaneous abortion were confirmed and this phenomenon needs further investigation.

In vivo characterization of pustules in Malassezia Folliculitis by reflectance confocal microscopy and optical coherence tomography. A case series study.

BACKGROUND AND OBJECTIVE: Malassezia Folliculitis (MaF) is an inflammatory condition of hair follicles caused by Malassezia yeast. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) are imaging technologies enabling in vivo visualization of superficial skin layers. This study explores morphology of pustules in MaF imaged by OCT and RCM. METHODS: Patients with microscopically verified MaF were included in this case series. Morphology was evaluated qualitatively with RCM and OCT, focusing on shape, border and content of selected pustules. RESULTS: Nine patients with MaF were included. Clinically, six patients presented monomorphic MaF with multiple superficial pustules, while three patients showed more polymorph MaF appearance. In total 13 pustules were investigated by RCM and OCT. In RCM images, pustules varied from having a well-defined border with homogenous content to ill-defined borders with heterogeneous content. A distinct black halo was occasionally observed around pustules as were dilated vessels. In OCT images, pustules appeared polymorphic, showing both well- and ill-defined structures with oval or irregular shape and more or less homogenous content. Malassezia fungi were not discernible by either RCM or OCT. Specific morphological image features in RCM and OCT did not reflect different clinical manifestations of MaF. CONCLUSION: RCM and OCT images identify morphological aspects of MaF pustules, and confirm that MaF is a folliculitis with clinical as well as morphological variance.

The long-term prognosis for live birth in couples initiating fertility treatments.

STUDY QUESTION: What are the long-term chances of having a child for couples starting fertility treatments and how many conceive with ART, IUI and without treatment? SUMMARY ANSWER: Total 5-year live birthrates were strongly influenced by female age and ranged from 80% in women under 35-26% in women ≥40 years, overall, 14% of couples conceived naturally and one-third of couples starting treatments with intrauterine insemination delivered from that treatment. WHAT IS KNOWN ALREADY: Few studies report success rates in fertility treatments across a couple's complete fertility treatment history, across clinics, evaluating live births after insemination, ART and natural conceptions. STUDY DESIGN, SIZE, DURATION: This register-based national cohort study from Denmark includes all women initiating fertility treatments in public and private clinics with homologous gametes in 2007-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were identified in the Danish ART Registry and were cross-linked with the Medical Birth Registry to identify live births. Subfertile couples were followed 2 years (N = 19 884), 3 years (N = 14 445) and 5 years (N = 5165), or until their first live birth. Cumulative live birthrates were estimated 2, 3 and 5 years from the first treatment cycle, in all women, including drop-outs. Birthrates were stratified by type of first treatment (ART/IUI), mode of conception (ART/IUI/natural conception) and female age. MAIN RESULTS AND THE ROLE OF CHANCE: Within 5 years, in women aged <35 years (N = 3553), 35-39 years (N = 1156) and ≥40 years (N = 451), a total of 64%, 49% and 16% had a live birth due to treatment, respectively. Additionally, in women aged < 35 years, 35-39 years and ≥40 years, 16%, 11% and 10% delivered after natural conception, yielding total 5-year birthrates of 80%, 60% and 26%. In women starting treatments with IUI (N = 3028), 35% delivered after IUI within 5 years, 24% delivered after shift to ART treatments and 17% delivered after natural conception. Within 5 years from starting treatments with ART (N = 2137), 53% delivered after ART, 11% delivered after natural conception and 0.6% delivered after IUI. LIMITATIONS, REASONS FOR CAUTION: Birthrates are most likely higher compared to countries without national coverage of treatments and results are influenced by laws and regulations. Information on duration of infertility prior to treatment was not available. Future prospective intervention studies should focus on the role of expectant management. WIDER IMPLICATIONS OF THE FINDINGS: Our results can provide couples with a comprehensible age-stratified prognosis at start of treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was unconditionally funded by Ferring Pharmaceuticals and the Augustinus foundation. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: S.S.M. received an unconditional grant from Ferring Pharmaceuticals; A.A.H. has received personal fees from Ferring Pharmaceuticals not related to this work; A.N.A. reports grants and personal fees from Ferring Pharmaceuticals, personal fees from Merck Serono, grants and personal fees from MSD, outside the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (J.nr. 2012-41-1330).

Cerebrospinal fluid biomarkers for Parkinson's disease - a systematic review.

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha-synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau-proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

Fever in pregnancy and the risk of congenital malformations: a cohort study.

BACKGROUND: In a variety of animal species, hyperthermia in pregnancy has been recognized as teratogenic. Hyperthermia interferes with protein synthesis via heat-shock proteins, which can entail membrane disruption, cell death, vascular disruption, and placental infarction. This can induce severe fetal malformations or death. Fever during pregnancy, especially during embryogenesis, has also been associated with congenital malformations in human offspring. The purpose of this large cohort study of clinically recognized pregnancies was to investigate whether fever during first trimester was associated with an increased risk of congenital malformations in the offspring. METHODS: The Danish National Birth Cohort is a population-based cohort of 100,418 pregnant women and their offspring recruited in 1996 to 2002. Information on fever during pregnancy was collected prospectively by means of two telephone interviews. The study population comprised the 77,344 pregnancies enrolled in the Danish National Birth Cohort where self-reported information on fever during first trimester of pregnancy was available. Pregnancy outcomes were identified through linkage with the National Patient Registry. Congenital malformations within the first three and a half years of life were categorized according to EUROCAT's classification criteria. Logistic regression models were used to estimate the associations between fever in first trimester and overall congenital malformations and congenital malformations by subgroups. RESULTS: Eight thousand three hundred twenty-one women reported fever during first trimester (10.8%) and 2876 infants were diagnosed with a congenital malformation (3.7%). Fever during first trimester did not affect the risk of overall fetal congenital malformation (OR 0.99, 95% CI 0.88-1.12). The subgroup analyses indicated slightly higher risk of congenital anomalies in the eye, ear, face and neck (OR 1.29, 95% CI 0.78-2.12) and in the genitals (OR 1.17, 95% CI 0.79-1.12), whereas lower risk of malformations in the nervous system (OR 0.47, 95% CI 0.21-1.08), the respiratory system (OR 0.56, 95% CI 0.23-1.29) and in the urinary subgroup (OR 0.58, 95% CI 0.35-0.99) was suggested, the latter constituting the only statistically significant finding. CONCLUSIONS: Overall, this study did not show any association between maternal fever in pregnancy and risk of congenital anomalies.