Atypicality index as an add-on to combined first-trimester screening for chromosomal aberrations.

OBJECTIVES: To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result. METHODS: The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. RESULTS: We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS < 80%), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%)), 1.52% (AcFTS [90-99%)) and 4.44% (AcFTS ≥ 99%) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS + EFW [90-99%) and AcFTS + EFW ≥ 99%, respectively). CONCLUSIONS: As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and ß-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Combined first-trimester screening and invasive diagnostics for atypical chromosomal aberrations: Danish nationwide study of prenatal profiles and detection compared with NIPT.

OBJECTIVES: Our aim was to examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy-number variants (pCNVs). We also wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these aberrations. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray analysis (CMA) to manage pregnancies identified as high risk by cFTS. METHODS: This was a retrospective review of the Danish Fetal Medicine Database of all pregnant women who underwent cFTS and a risk assessment for trisomy 21 between 1 January 2008 and 31 December 2018. Chromosomal aberrations diagnosed prenatally, postnatally or from fetal tissue following pregnancy loss or termination of pregnancy were identified. Chromosomal aberrations were grouped into one of six categories: triploidy; common trisomy (13, 18 or 21); monosomy X; other sex-chromosome aberration (SCA); pCNV; and rare autosomal trisomy (RAT) or mosaicism. The prevalence of each aberration category was stratified by the individual cFTS markers and trisomy 21 risk estimate, and the size of each pCNV diagnosed by CMA was calculated. RESULTS: We retrieved data on 565 708 pregnancies, of which 3982 (0.70%) were diagnosed with a fetal chromosomal aberration. cFTS identified 87% of the common trisomies, but it also performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%) and RATs or mosaicisms (70%). pCNVs comprised 27% (n = 1091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period, as prenatal CMA was increasingly being performed. In pregnancies with a maternal age < 30 years, nuchal translucency (NT) thickness ≤ 95th centile, pregnancy-associated plasma protein-A (PAPP-A) ≥ 1 multiple of the median, or trisomy 21 risk of ≤ 1 in 1000, the prevalence of pCNVs exceeded significantly the prevalence of trisomies 21, 18 and 13. Pregnancies affected by a pCNV had significantly increased NT and decreased levels of the maternal biomarkers PAPP-A and ß-human chorionic gonadotropin compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive on cFTS and 51% of pCNVs were not detected until after birth. Among high-risk pregnancies, pCNVs comprised 14% of diagnosed aberrations, and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18 and 13 and monosomy X) would miss 27% of all pathogenic aberrations diagnosed from invasive testing following a high-risk cFTS result. Thus, 1 in 26 pregnancies at high risk following cFTS would be affected by a chromosomal aberration despite a normal result from conventional NIPT. In a contingent screening model using NIPT for the 'intermediate'-risk group (trisomy 21 risk of 1 in 100-299), 50% of the aberrations would be missed. In our cohort, 79% of the pCNVs diagnosed were < 5Mb and therefore not detectable using current forms of 'genome-wide' NIPT. CONCLUSIONS: As a by-product of screening for trisomies 21, 18 and 13, most triploidies and the majority of atypical SCAs, RATs and mosaicisms are detected before birth. However, only 23% of pCNVs are associated with a high-risk result according to cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high-risk pregnancies would substantially decrease the first-trimester detection of pathogenic chromosomal anomalies. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

OBJECTIVES: To examine the distribution of nuchal translucency thickness (NT), free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. METHODS: This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and ß-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. RESULTS: We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). ß-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. CONCLUSIONS: The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and ß-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Social network analysis reveals the failure of between-farm movement restrictions to reduce Salmonella transmission.

An increasing number of countries are investigating options to stop the spread of the emerging zoonotic infection Salmonella Dublin (S. Dublin), which mainly spreads among bovines and with cattle manure. Detailed surveillance and cattle movement data from an 11-yr period in Denmark provided an opportunity to gain new knowledge for mitigation options through a combined social network and simulation modeling approach. The analysis revealed similar network trends for noninfected and infected cattle farms despite stringent cattle movement restrictions imposed on infected farms in the national control program. The strongest predictive factor for farms becoming infected was their cattle movement activities in the previous month, with twice the effect of local transmission. The simulation model indicated an endemic S. Dublin occurrence, with peaks in outbreak probabilities and sizes around observed cattle movement activities. Therefore, pre- and postmovement measures within a 1-mo time window may help reduce S. Dublin spread.

Longitudinal changes of serum cytokines in patients with chronic low back pain and Modic changes.

OBJECTIVES: To explore serum cytokine levels over time in patients with chronic low back pain (cLBP) and Modic changes (MCs), difference in change between treatment groups in the Antibiotics in Modic Changes (AIM) study and associations between change in cytokines and low back pain. METHODS: Serum concentrations of 39 cytokines were measured at baseline and 1 year from 73 participants in the AIM study; 30 randomized to placebo, 43 to Amoxicillin. Low back pain intensity was measured by numeric rating scale. Change in cytokine levels over time were assessed by paired t-tests. Difference in change in cytokine levels between treatment groups and associations between changes in LBP and cytokine levels were assessed by linear regression models. Networks of cytokine changes in each treatment groups were explored by Pearson's correlations. RESULTS: Five cytokines changed from baseline to 1 year, (mean change, log transformed values with CI) C-X-C motif chemokine ligand (CXCL) 10 (IP-10) (0.11 (0.01-0.20)), CXCL13 (0.61 (0.00-0.12)), C-C motif chemokine ligand (CCL)26 (0.05 (0.01-0.1)), granulocyte macrophage-colony stimulating factor (GM-CSF) (-0.12 (-0.23 to 0.00)) and CXCL11 (0.12 (0.03-0.22)). Treatment group only influenced change in CCL21 (ß 0.07 (0.01-0.12)), and IL-6 (ß -0.17 (-0.30 to -0.03)). Change in CXCL13 (ß 2.43 (0.49-4.38)), CCL27 (ß 3.07 (0.46-5.69)), IL-8 (ß 1.83 (0.08-3.58)) and CCL19 (ß 3.10 (0.86-5.43)) were associated with change in LBP. The correlation networks of cytokine changes demonstrate small differences between treatment groups. CONCLUSIONS: Cytokine levels are relatively stable over time in our sample, with little difference between treatment groups. Some cytokines may be associated with LBP intensity. The differences between the correlation networks suggest that long-term Amoxicillin-treatment may have longstanding effects to be further explored.

Venous thromboembolism in cancer patients: a population-based cohort study.

The incidence of venous thromboembolism (VTE) in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499 092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1 497 276 comparison individuals without cancer from the general population. We computed cumulative incidences of VTE 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing-risk analysis. Cumulative incidence of VTE 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval [CI], 2.2% to 2.3%) in the cancer cohort and 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior VTE (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI, 3.4-4.9), antiangiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9% to 1.2%) in 1997 to 3.4% (95% CI, 2.9% to 4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography scans, chemotherapy, and targeted therapies. In conclusion, the risk of VTE in cancer patients is increasing steadily and is ninefold higher than in the general population.

Atypicality index: avoiding false reassurance in prenatal screening.

OBJECTIVE: To demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test. METHODS: This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free ß-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index. RESULTS: In pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of < 80%. Similarly, in high-risk pregnancies, the incidence of adverse outcome was 7.9 (95% CI, 4.4-14.5) times higher in those with an atypicality index of ≥ 99% compared to those with an atypicality index of < 80%. Using individual profile plots, we were able to demonstrate a transparent and intuitive method for visualization of multiple variables, which can help interpret the individual combination of measurements and level of atypicality. CONCLUSIONS: In pregnancies undergoing first-trimester combined screening and classified as being at low risk for major trisomies, profiles that are typical of pregnancies with normal outcome provide additional reassurance, whereas those with an atypical profile may warrant further investigation. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Comprehensive Test of the Brink-Axel Hypothesis in the Energy Region of the Pygmy Dipole Resonance.

The validity of the Brink-Axel hypothesis, which is especially important for numerous astrophysical calculations, is addressed for ^{116,120,124}Sn below the neutron separation energy by means of three independent experimental methods. The γ-ray strength functions (GSFs) extracted from primary γ-decay spectra following charged-particle reactions with the Oslo method and with the shape method demonstrate excellent agreement with those deduced from forward-angle inelastic proton scattering at relativistic beam energies. In addition, the GSFs are shown to be independent of excitation energies and spins of the initial and final states. The results provide a critical test of the generalized Brink-Axel hypothesis in heavy nuclei, demonstrating its applicability in the energy region of the pygmy dipole resonance.

Antidepressant use in pregnancy and severe cardiac malformations: Danish register-based study.

OBJECTIVE: Studies restricted to live births may underestimate severe teratogenic effects. We address the limitation by including data from both prenatal and postnatal diagnoses of cardiac malformations. DESIGN: Register-based study. SETTING: Denmark. POPULATION: 364 012 singleton pregnancies from 2007 to 2014. METHODS: We used data from five nationwide registries. Exposure to antidepressants was measured using redeemed prescriptions. MAIN OUTCOME MEASURES: Pregnancies with cardiac malformations that end in miscarriage, termination, stillbirth, postnatal death or cardiac surgery <1 year of birth were classified as severe cardiac malformations (SCM). Propensity scores with adjusted prevalence ratios (PRs) were calculated. RESULTS: SCM were reported in 972 of 364 012 pregnancies overall and in 16 of 4105 exposed. For venlafaxine, the PR for SCM was 2.13 (95% confidence interval [CI] 0.89-5.13), 1.73 (95% CI 1.08-2.77) for other cardiac malformations, and there was a cluster of hypoplastic left heart syndromes (HLHS) (crude PR 17.4 [95% CI 6.41-47.2]), none of which ended in a live birth. For HLHS, the absolute risk increase was 4.4/1000 and the number needed to harm was 225. For selective serotonin reuptake inhibitors, the PRs were 1.09 (95% CI 0.52-2.30) and 1.38 (95% CI 1.00-1.92) for SCM and other cardiac malformations, respectively. CONCLUSIONS: Pregnancy exposure to venlafaxine is associated with an increased risk of severe cardiac malformations but with a low absolute risk. Potential mechanisms include direct effects or confounding by indication. Venlafaxine exposure is a marker for risk pregnancies for which fetal echocardiography may be considered. TWEETABLE ABSTRACT: Exposure to venlafaxine is associated with an increased risk of cardiac malformations but with a low absolute risk.

General practitioners' perceived indicators of vulnerability in pregnancy- A qualitative interview study.

OBJECTIVE: To explore general practitioners' (GPs') perceived indicators of vulnerability among pregnant women in primary care. DESIGN: A qualitative study with semi-structured in-depth focus group interviews. SETTING: General practices located in a mixture of urban, semi-urban and rural practices throughout the Region of Southern Denmark SUBJECTS: Twenty GPs. MAIN OUTCOME MEASURES: Through qualitative analysis with systematic text condensation of the interview data, the following themes emerged: (1) obvious indicators of vulnerability-i.e. somatic or psychological illnesses, or complex social problems and 2) intangible indicators of vulnerability - i.e. identification depended on the GPs' gut-feeling. From the GPs' perspective, the concept of vulnerability in pregnancy were perceived as the net result of risk factors and available individual and social resources, with a psychosocial etiology as the dominant framework. CONCLUSIONS: The GPs demonstrated a broad variety of perceived indicators of vulnerability in pregnancy; most importantly, the GPs were aware of a group of pregnant women with intangible vulnerability mainly representing low resilience. Despite not fitting into the GPs' perceived concept of vulnerability, the GPs had a strong gut feeling that these women might be vulnerable. Misjudging the resources of pregnant women due to their physical appearance could delay the GPs' identification of vulnerability. Future studies should explore the challenges GPs experiences when assessing vulnerability among pregnant women.

Comparative cardiovascular safety of strontium ranelate and bisphosphonates: a multi-database study in 5 EU countries by the EU-ADR Alliance.

Strontium ranelate use, compared with oral bisphosphonates, is not associated with increased risk of AMI in patients with no contraindications for SR use. However, current strontium ranelate (compared with current bisphosphonate) appears associated with 25-30% excess risk of VTE and 35% excess risk of CVDeath. INTRODUCTION: Evaluate the risk of cardiac and thromboembolic events among new users of SR and oral BPs without contraindications for SR. METHODS: We conducted three multi-national, multi-database (Aarhus-Denmark, HSD-Italy, IPCI-Netherlands, SIDIAP-Spain, THIN-UK) case-control studies nested within a cohort of new users of SR/BP. We matched cases of acute myocardial infarction (AMI), venous thromboembolism (VTE), and cardiovascular death (CVDeath), up to 10 controls on gender, year of birth, index date, and country. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) according to current SR vs current BP use and current vs past SR use, adjusting for potential confounders. Data were pooled using random effects meta-analysis. RESULTS: No excess risk of AMI (5477 cases/54,674 controls) was found with current SR vs current BP (OR 0.89 (95%CI 0.70, 1.12)) nor with current vs past SR use (0.71(0.56, 0.91)). For VTE (5614 cases/6036 controls), an excess risk was found with current SR compared with current BP use, 1.24 (0.96, 1.61), and current vs past SR use, 1.30 (1.04, 1.62). For CVDeath (3019 cases/29,871 controls), an increased risk was seen with current SR vs current BP use, 1.35 (1.02, 1.80), but not with current vs past SR use (0.68 (0.48, 0.96)). CONCLUSION: In patients without contraindications for SR, we found no evidence of an increased risk of AMI but a 25-30% excess risk of VTE and a 35% excess risk of CVDeath with current SR vs current BP users. This is despite a reduction in risk in CVDeath with current vs past SR users. The latter disparity could still be partially explained by cessation of preventative therapies in end-of-life or residual confounding by indication.

Correction to: Impact of risk minimisation measures on the use of strontium ranelate in Europe: a multi-national cohort study in 5 EU countries by the EU-ADR Alliance.

The original version of this article, published on 26 November 2019 contained a mistake.

Impact of risk minimisation measures on the use of strontium ranelate in Europe: a multi-national cohort study in 5 EU countries by the EU-ADR Alliance.

INTRODUCTION: In May 2013 and March 2014, the European Medicines Agency (EMA) issued two decisions restricting the use of strontium ranelate (SR). These risk minimisation measures (RMM) introduced new contraindications and limited the indications of SR therapy. The EMA required an assessment of the impact of RMMs on the use of SR in Europe. Methods design: multi-national, multi-database cohort Setting: electronic medical record databases based on hospital (Denmark) and primary care provenance (Italy, Spain, the Netherlands, UK). PARTICIPANTS: the database source populations were included for population-based analyses, and SR users for patient-level analyses. INTERVENTION: New RMMs included contraindications (ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, uncontrolled hypertension) and restricted SR indication to severe osteoporosis with initiation by experienced physician and not as first line anti-osteoporosis therapy. METHODS: Prevalence and incidence rates of SR use in the population; prevalence of contraindications and restricted indications in SR users, plus 1-year therapy persistence. Drug use measures were calculated in three periods for comparison: reference (2004 to May 2013), transition (June 2013 to March 2014) and assessment (from April 2014 to end 2016). RESULTS: The study population included 143 million person-years(PY) of follow-up and 76,141 incident episodes of SR treatment. Average monthly prevalence rates of SR use dropped by 86.4% from 62.6/10,000 PY (95 CI 62.4-62.9) in the reference to 8.5 (8.5-8.6) in the assessment period. Similarly, the incidence rate of SR use fell by 97.3% from 7.4/10,000 PY (7.4-7.4) to 0.2 (0.2-0.2) between the reference and assessment period. The prevalence of any contraindication decreased, whilst the prevalence of restricted indications increased in these periods. One-year persistence decreased in the assessment compared with reference period. CONCLUSIONS: Our study demonstrates a substantial impact of the regulatory action to restrict use of SR in Europe: SR utilisation overall decreased strongly. The proportion of patients fulfilling the restricted indications, without contraindications, increased after the proposed RMMs.

Evolution of Octupole Deformation in Radium Nuclei from Coulomb Excitation of Radioactive

There is sparse direct experimental evidence that atomic nuclei can exhibit stable "pear" shapes arising from strong octupole correlations. In order to investigate the nature of octupole collectivity in radium isotopes, electric octupole (E3) matrix elements have been determined for transitions in ^{222,228}Ra nuclei using the method of sub-barrier, multistep Coulomb excitation. Beams of the radioactive radium isotopes were provided by the HIE-ISOLDE facility at CERN. The observed pattern of E3 matrix elements for different nuclear transitions is explained by describing ^{222}Ra as pear shaped with stable octupole deformation, while ^{228}Ra behaves like an octupole vibrator.

Neurodevelopmental disorder in children believed to have isolated mild ventriculomegaly prenatally.

OBJECTIVE: To estimate the prevalence of specific neurodevelopmental disorders in children believed to have isolated mild ventriculomegaly (IMV) prenatally in the second trimester of pregnancy, in order to optimize the counseling process. METHODS: This was a nationwide registry-based study including all singleton pregnancies that had first- and second-trimester ultrasound scans in the period 1st January 2008 to 1st October 2014, identified in the Danish Fetal Medicine Database and local clinical databases in Denmark. All fetuses diagnosed prenatally with IMV (measurement of the atrium of the lateral ventricles, 10.0-15.0 mm) between 18 and 22 weeks' gestation were followed up in national patient registers until the age of 2-7 years. Information was obtained on the diagnoses of intellectual disability, cerebral palsy, autism spectrum disorder, epilepsy and impaired psychomotor development. Neurodevelopmental disorders were compared between those with postnatally confirmed IMV and a reference population of children in the same age range. RESULTS: Of a cohort of 292 046 fetuses, 133 were found to have apparent IMV on the second-trimester scan for fetal malformations. In 11 cases, long-term follow-up was not possible owing to termination of pregnancy, spontaneous miscarriage, neonatal death or loss to follow-up. Of the 122 liveborn children followed up until 2-7 years, 15 were identified as having an additional abnormality while 107 were confirmed postnatally to have IMV. Of these 107 children, the diagnosis of a neurodevelopmental disorder was registered in six (5.6%), corresponding to an odds ratio of 2.64 (95% CI, 1.16-6.02), as compared with the reference population. The diagnoses were autism spectrum disorder, epilepsy and impaired psychomotor development. None of these 107 children was diagnosed with intellectual disability or cerebral palsy. CONCLUSIONS: Our results show that a confirmed diagnosis of IMV was associated with an increased risk of a neurodevelopmental disorder, as compared with the reference population, but the absolute risk was low and there were no cases of intellectual disability or cerebral palsy. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Trastorno del desarrollo neurológico en fetos con sospecha de ventriculomegalia leve aislada prenatal OBJETIVO: Estimar la prevalencia de trastornos específicos del desarrollo neurológico en fetos con sospecha de ventriculomegalia leve aislada (IMV, por sus siglas en inglés) prenatal en el segundo trimestre del embarazo, a fin de optimizar el proceso de asesoramiento. MÉTODOS: Este estudio estuvo basado en un registro nacional que incluyó todos los embarazos con feto único a los que se les hizo ecografías en el primer y segundo trimestre entre el 1 de enero de 2008 y el 1 de octubre de 2014, identificados en la Base de Datos Danesa de Medicina Fetal y en las bases de datos clínicas locales en Dinamarca. Todos los fetos diagnosticados prenatalmente con IMV (por medición de la aurícula de los ventrículos laterales, 10,0-15,0 mm) entre las semanas de gestación 18 y 22 fueron monitoreados en los registros nacionales de pacientes hasta la edad de 2-7 años. Se obtuvo información sobre los diagnósticos de discapacidad intelectual, parálisis cerebral, trastornos del espectro autista, epilepsia y trastornos del desarrollo psicomotor. Se compararon los trastornos del desarrollo neurológico entre aquellos con IMV confirmada después del nacimiento y una población de referencia de niños en el mismo rango de edad. RESULTADOS: De una cohorte de 292 046 fetos, se encontró que 133 tenían IMV aparente en la ecografía del segundo trimestre realizada para detectar malformaciones fetales. El seguimiento a largo plazo no fue posible en 11 casos debido a la interrupción del embarazo, el aborto espontáneo, la muerte del recién nacido o el abandono del monitoreo. De los 122 niños nacidos vivos a los que se les dio seguimiento hasta los 2-7 años, se identificó a 15 con una anomalía adicional, mientras que a 107 se les confirmó postnatalmente que tenían IMV. De estos 107 niños, se registró el diagnóstico de un trastorno del desarrollo neurológico en seis (5,6%), lo que corresponde a una razón de momios de 2,64 (IC 95%: 1,16-6,02), en comparación con la población de referencia. Los diagnósticos fueron trastornos del espectro autista, epilepsia y trastornos del desarrollo psicomotor. Ninguno de estos 107 niños fue diagnosticado con discapacidad intelectual o parálisis cerebral. CONCLUSIONES: Nuestros resultados muestran que un diagnóstico confirmado de IMV se asoció con un mayor riesgo de trastorno del desarrollo neurológico, en comparación con la población de referencia, pero que el riesgo absoluto fue bajo y no hubo casos de discapacidad intelectual o parálisis cerebral.

Research protocol of two concurrent cluster-randomized trials: Real-life Effect of a CAMPaign with Measles Vaccination (RECAMP-MV) and Real-life Effect of a CAMPaign with Oral Polio Vaccination (RECAMP-OPV) on mortality and morbidity among children in rural Guinea-Bissau.

BACKGROUND: Measles and oral polio vaccinations may reduce child mortality to an extent that cannot be explained by prevention of measles and polio infections; these vaccines seem to have beneficial non-specific effects. In the last decades, billions of children worldwide have received measles vaccine (MV) and oral polio vaccine (OPV) through campaigns. Meanwhile the under-five child mortality has declined. Past MV and OPV campaigns may have contributed to this decline, even in the absence of measles and polio infections. However, cessation of these campaigns, once their targeted infections are eradicated, may reverse the decline in the under-five child mortality. No randomized trial has assessed the real-life effect of either campaign on child mortality and morbidity. We present the research protocol of two concurrent trials: RECAMP-MV and RECAMP-OPV. METHODS: Both trials are cluster-randomized trials among children registered in Bandim Health Project's rural health and demographic surveillance system throughout Guinea-Bissau. RECAMP-MV is conducted among children aged 9-59 months and RECAMP-OPV is conducted among children aged 0-8 months. We randomized 222 geographical clusters to intervention or control clusters. In intervention clusters, children are offered MV or OPV (according to age at enrolment) and a health check-up. In control clusters, children are offered only a health check-up. Enrolments began in November 2016 (RECAMP-MV) and March 2017 (RECAMP-OPV). We plan 18,000 enrolments for RECAMP-MV with an average follow-up period of 18 months and 10,000 enrolments for RECAMP-OPV with an average follow-up period of 10 months. Data collection is ongoing. The primary outcome in both trials is non-accidental death or non-accidental first non-fatal hospitalization with overnight stay (composite outcome). Secondary outcomes are: non-accidental death, repeated non-fatal hospitalizations with overnight stay, cause-specific primary outcome, outpatient visit, and illness. We obtained ethical approval from Guinea-Bissau and consultative approval from Denmark. DISCUSSION: Cluster randomization and minimum risk of loss to follow-up are strengths, and no placebo a limitation. Our trials challenge the understanding that MV and OPV only prevent measles and polio, and that once both infections are eradicated, campaigns with MV and OPV can be phased out without negative implications on child health and survival. TRIAL REGISTRATION: NCT03460002.

Hyperkalaemia in people with diabetes: occurrence, risk factors and outcomes in a Danish population-based cohort study.

AIMS: To examine the incidence, risk factors and clinical outcomes of hyperkalaemia in people with diabetes in a real-world setting. METHODS: Using Danish health registries, we identified a population-based cohort of people with first-time drug-treated diabetes, in the period 2000-2012. First, the cumulative incidence of hyperkalaemia, defined as first blood test with potassium level >5.0 mmol/l after diabetes treatment initiation, was ascertained. Second, in a case-control analysis, risk factors were compared in people with vs without hyperkalaemia. Third, clinical outcomes were assessed among individuals with hyperkalaemia in a before-after analysis, and among people with and without hyperkalaemia in a matched cohort analysis. RESULTS: Of 68 601 individuals with diabetes (median age 62 years, 47% women), 16% experienced hyperkalaemia (incidence rate 40 per 1000 person-years) during a mean follow-up of 4.1 years. People who developed hyperkalaemia had a higher prevalence of chronic kidney disease [prevalence ratio 1.74 (95% CI 1.68-1.81)], heart failure [prevalence ratio 2.35 (95% CI 2.18-2.54)], use of angiotensin-converting enzyme inhibitors [prevalence ratio 1.24 (95% CI 1.20-1.28)], use of spironolactone [prevalence ratio 2.68 (95% CI 2.48-2.88)] and potassium supplements [prevalence ratio 1.59 (95% CI 1.52-1.67)]. In people with diabetes who developed hyperkalaemia, 31% were acutely hospitalized within 6 months before hyperkalaemia, increasing to 50% 6 months after hyperkalaemia [before-after risk ratio 1.67 (95% CI 1.61-1.72)]. The 6-month mortality rate after hyperkalaemia was 20%. Compared with matched individuals without hyperkalaemia, the hazard ratio for death was 6.47 (95% CI 5.81-7.21). CONCLUSIONS: One in six newly diagnosed people with diabetes experienced a hyperkalaemic event, which was associated with severe clinical outcomes and death.

The causal role of smoking on the risk of headache. A Mendelian randomization analysis in the HUNT study.

BACKGROUND AND PURPOSE: Headache has been associated with various lifestyle and psychosocial factors, one of which is smoking. The aim of the present study was to investigate whether the association between smoking intensity and headache is likely to be causal. METHOD: A total of 58 316 participants from the Nord-Trøndelag Health (HUNT) study with information on headache status were genotyped for the rs1051730 C>T single-nucleotide polymorphism (SNP). The SNP was used as an instrument for smoking intensity in a Mendelian randomization analysis. The association between rs1051730 T alleles and headache was estimated by odds ratios with 95% confidence intervals. Additionally, the association between the SNP and migraine or non-migrainous headache versus no headache was investigated. All analyses were adjusted for age and sex. RESULTS: There was no strong evidence that the rs1051730 T allele was associated with headache in ever smokers (odds ratio 0.99, 95% confidence interval 0.95-1.02). Similarly, there was no association between the rs1051730 T allele and migraine or non-migrainous headache versus no headache. CONCLUSION: The findings from this study do not support that there is a strong causal relationship between smoking intensity and any type of headache. Larger Mendelian randomization studies are required to examine whether higher smoking quantity can lead to a moderate increase in the risk of headache subtypes.

Cerebral oximetry during preoperative resuscitation in elderly patients with hip fracture: a prospective observational study.

This study explores the association between postadmission and intraoperative cerebral oxygenation (ScO2), reflecting systemic perfusion, and postoperative mortality and delirium. Forty elderly (age > 65 years) patients with hip fractures were included in this prospective observational study. The ScO2 was determined using near-infrared spectroscopy at initial resuscitation after patients were admitted to the hospital and during surgery. Postoperative delirium was assessed up to seven days after surgery using the memorial delirium assessment scale and the confusion assessment method. Ten patients (25%) developed postoperative delirium within the first seven postoperative days. At initial resuscitation ScO2 was lower in patients that later developed delirium, but the difference was not significant (p = 0.331). Intraoperative ScO2 values remained similar in the two groups. Mortality regardless of cause was 10% (4 out of 40 patients) after 30 days. At initial resuscitation ScO2 was significant lower in the mortality group than in the surviving group (p = 0.042), and the ScO2 nadir values were also significant lower (p = 0.047). Low ScO2 during initial resuscitation (defined as ScO2 < 55 for a minimum of two consecutive minutes) was also significantly associated with 30-day mortality (p = 0.015). There were no associations between low blood pressure and postoperative delirium or 30-day mortality. We found that low preoperative ScO2 was better associated with 30-day all-cause mortality in elderly patients undergoing surgery for hip fracture than blood pressure measurements. Future studies in preoperative resuscitation of hip fracture patients should focus on perfusion measures as opposed to conventional haemodynamic.