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

OBJECTIVE: To examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy number variants (pCNVs). Further, we wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these conditions. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray (CMA) to manage pregnancies identified as high risk from cFTS. METHODS: A retrospective review of the Danish fetal medicine database identified all pregnant women who had cFTS and a trisomy 21 risk-assessment between January 1, 2008, and December 31, 2018. Chromosomal aberrations diagnosed prenatally, postnatally, or from fetal tissue following pregnancy loss or termination of pregnancy (TOP) were identified. Chromosomal aberrations were grouped into one of six categories: 1) Triploidy; 2) Common trisomies (trisomies 21, 18, and 13); 3) Monosomy X; 4) Other sex chromosome aberrations (SCAs); 5) pCNVs; and 6) Rare autosomal trisomies (RATs) and mosaicisms. The prevalence of each aberration-category was stratified by the individual cFTS markers and risk estimate, and the size of each pCNV diagnosed from CMA was calculated. RESULTS: We included data on 565,708 pregnancies of which 3,982 were diagnosed with a fetal chromosomal aberration (0.70%). cFTS performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%), and RATs and mosaicisms (70%). pCNVs comprised 28% (n = 1,091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period with more prenatal chromosomal microarray analysis being performed. In pregnancies with maternal age <30 years, NT <95th percentile, PAPP-A MoM ≥ 1, or trisomy 21 risk ≥1 in 1000, the prevalence of pCNVs significantly exceeded the prevalence of trisomies 21, 18, and 13. Pregnancies affected by a pCNV had significantly increased nuchal translucency thickness (NT) and decreased maternal biomarkers pregnancy associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-hCG) compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive from cFTS and 51% were not detected until after birth. Amongst high-risk pregnancies diagnosed with a chromosomal aberration, pCNVs comprised 14% and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18, and 13, and monosomy X) would miss 28% of all pathogenic aberrations diagnosed 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 conventional NIPT result. In a contingent screening model with NIPT provided for the "intermediate" risk group (T21 risk of 1 in 100-300), 50% of the aberrations would be missed. In our cohort, 80% of the pCNVs diagnosed were <5Mb and therefore not detectable using current forms of "genome wide" NIPT. CONCLUSION: As a by-product to 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 high-risk from 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. This article is protected by copyright. All rights reserved.

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.

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

OBJECTIVES: To compute a set of atypicality indices from combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at either reduced or increased risks 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 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 of pregnancy were identified. A first-trimester atypicality index (AcFTS ) was computed from nuchal translucency (NT) thickness, maternal serum free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Further, a second trimester index (AcFTS+EFW ) was computed from cFTS markers and estimated fetal weight (EFW) estimated at 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 multivariate measurement profiles was introduced. RESULTS: We retrieved data on 145,955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 of all pregnancies seen for cFTS (0.82% [95% CI 0.77-0.87%]) were affected by a fetal chromosomal aberration and in screen-negative pregnancies (cFTS T21 risk <1 in 100 and/or T18/13 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 to 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 (AcFTS+EFW ) 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 act as reassurance, whereas atypical profiles may warrant specialist referral and further investigations. In pregnancies at low risk from 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. This article is protected by copyright. All rights reserved.

Volcanic evolution of an ultraslow-spreading ridge.

Nearly 30% of ocean crust forms at mid-ocean ridges where the spreading rate is less than 20 mm per year. According to the seafloor spreading paradigm, oceanic crust forms along a narrow axial zone and is transported away from the rift valley. However, because quantitative age data of volcanic eruptions are lacking, constructing geological models for the evolution of ultraslow-spreading crust remains a challenge. In this contribution, we use sediment thicknesses acquired from ~4000 km of sub-bottom profiler data combined with 14C ages from sediment cores to determine the age of the ocean floor of the oblique ultraslow-spreading Mohns Ridge to reveal a systematic pattern of young volcanism outside axial volcanic ridges. Here, we present an age map of the upper lava flows within the rift valley of a mid-ocean ridge and find that nearly half of the rift valley floor has been rejuvenated by volcanic activity during the last 25 Kyr.

Virtual reality increases pressure pain threshold and lowers anxiety in children compared with control and non-immersive control-A randomized, crossover trial.

BACKGROUND: Virtual reality (VR) is a promising non-pharmacological pain intervention because it may not only distract but also modulate pain by immersing the user in a three-dimensional 360° alternate reality. In children, VR has been reported to reduce clinical pain and anxiety during medical procedures. However, the effect of immersive VR on pain and anxiety remains to be investigated in randomized controlled trials (RCT). The aim of the present crossover RCT was to assess the effect of VR on pressure pain threshold (PPT) and anxiety level measured with the modified Yale Preoperative Anxiety Scale (mYPAS) in children in a controlled experimental setting. METHODS: Seventy-two children (mean age 10.2 (6-14) years) were randomized to 24 sequences of four interventions (immersive VR Game, immersive VR video, tablet: 2D video and control: small talk). Outcome measures PPT, mYPAS and heart rate were assessed before and after each intervention. RESULTS: PPT increased significantly during VR game (PPTdiff): 136 kPa (CI 112; 161), p < 0.0001 and VR Video (PPTdiff): 122 kPa (CI 91; 153), p < 0.0001. Also, anxiety levels significantly decreased during both VR game (mYPASdiff: -7 points (-8 to -5), p < 0.0001) and VR video (mYPASdiff: -6 points (CI -7; -4), p < 0.0001). CONCLUSIONS: VR had a marked beneficial effect on PPT and anxiety compared with the control interventions: 2D video and small talk. Thus, immersive VR had a distinct modulatory effect on pain and anxiety in a well-controlled experimental setting. Immersive VR was effective and feasible in children and can act as a valid tool for non-pharmacological pain and anxiety management. SIGNIFICANCE: Paediatric immersive VR seems to be beneficial although well-controlled studies are pending. We investigated whether immersive VR can modulate children's threshold for pain and anxiety level in an experimental well-controlled setting. We document a modulatory pain threshold increase and anxiety level decrease compared with extensive control conditions. Paediatric immersive VR is effective, feasible and valid for non-pharmacological pain and anxiety management. All efforts to reach the goal that no child should experience pain or anxiety when exposed to medical procedures.

GPs' prescription patterns, experience, and attitudes towards medicinal cannabis-a nationwide survey at the early stage of the Danish test scheme.

BACKGROUND: On 1 January 2018 a four-year test scheme concerning use of medicinal cannabis (MC) was enacted. It has recently been extended for four more years by the Danish Parliament permitting all Danish physicians to prescribe MC to their patients. Previous studies have shown that general practitioners (GPs) have varying prescription experience, little knowledge, and mixed attitudes about MC. However, the present evidence is still limited, and no studies exist about Danish GPs' prescription experience, knowledge, and attitudes towards MC. Therefore, our aim was to examine Danish GPs' prescription experience, knowledge, and attitudes towards MC. METHODS: A national online survey-based study addressing Danish GPs was performed from September 2018 to July 2019. We performed separate multivariable logistic regression analyses including GPs' prescription experience, knowledge, and attitudes towards MC as outcome variables. RESULTS: A total of 427 (38.4%) of 1112 GPs completed the questionnaire. Of these, 37 (8.7%) had experience in prescribing MC. The majority had little or no knowledge about MC (80.6%) as well as a negative view on prescription of MC (71.4%) to patients. Factors associated with prescribing MC to patients were: Single-handed practices (OR = 1.6, 95% CI 1.1;1.8) and perception of having quite some knowledge about MC (OR = 4.8, 95% CI 2.2;10.4). Factors associated with having quite some knowledge about MC were: having a positive attitude towards prescribing MC (OR = 5.2, 95% CI 1.9;14.0), being male (OR = 1.7, 95% CI 1.4;1.8), and being at least 60 years of age (OR = 2.8, 95% CI 1.3;6.0). Factors associated with having a positive attitude towards prescribing MC were: having quite some knowledge about MC (OR = 5.2, 95% CI 2.2;12.5) and GPs being male (OR = 1.7, 95% CI 1.1;1.9). CONCLUSION: In this first study on prescription experience, knowledge, and attitudes about MC among Danish GPs, conducted one year after the Danish test scheme was enacted, we find a very low proportion of prescribers, little knowledge, and an overall negative attitude towards MC. Among the prescribing GPs, four in ten have little to no knowledge and a negative attitude towards MC. We stress that prescribing patterns, knowledge, and attitudes may change throughout the remaining time of the test scheme.

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.

Postweaning growth and feeding behaviour in pigs: effect of heavier hybrid and weaning intact litters in farrowing pens for loose-housed sows.

Abrupt weaning of four-week-old pigs is associated with multiple stressors. Housing pigs in intact litters is a way to reduce the stress associated with moving and mixing of unfamiliar pigs. Furthermore, higher weaning weight may improve pigs' robustness against postweaning stressors. In the present study, it was investigated whether: (1) A heavier pig hybrid, and (2) weaning intact litters in the farrowing pen for loose-housed sows could increase postweaning feeding behaviour and growth. Two sow hybrids (DanBred LY (DB) and Topigs Norsvin TN70 (TN)) and two weaning strategies (the litter stayed intact in the farrowing pen after removing the sow (STAY), or two litters were moved and mixed in conventional weaner pens (MOVE)) were compared in a 2 × 2 factorial design. In total, 57 litters from four batches were included in the study. The TN hybrid sows gave birth to heavier piglets but smaller litter sizes and had more functional teats than DB sows. At weaning, TN pigs were heavier than DB. The number of feed trough (FT) visits on the day before weaning was low in both hybrids. On the day after weaning, the number of FT visits was higher in MOVE compared to STAY, and in TN-STAY compared to DB-STAY. The average daily gain the first two days postweaning was negative in both hybrids and weaning strategies but more pronounced in DB than TN, and STAY tended to lose more weight than MOVE. Over the entire 28-day postweaning period, there was an interaction between hybrid and weaning strategy in that TN-STAY (392 g/d) had higher growth than both TN-MOVE (251 g/d) and DB-MOVE (283 g/d), whereas growth of DB-STAY (316 g/d) was intermediate. In addition, higher weaning weight was associated with a lower number of FT visits and greater weight loss the first two days postweaning but higher growth over the 28-day postweaning period. The results show that abrupt weaning at four weeks of age causes weight loss the first days postweaning despite being housedas intact litters, most likely due to low feed consumption. However, the combination of a heavier pig hybrid and housing intact litters in the farrowing pen postweaning resulted in a higher growth performance over the 28-day postweaning period. In conclusion, pigs that are heavier at weaning reach better growth performance in the longer term, despite having the largest acute postweaning growth depression and fewest FT visits on the day before and after weaning.

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.

La realidad virtual eleva el umbral de dolor por presión y reduce la ansiedad en niños comparada con controles y controles no inmersivos. Un estudio aleatorizado y cruzado / Virtual reality increases pressure pain threshold and lowers anxiety in children compared with control and non-immersive control-randomized, crossover trial

Antecedentes: La realidad virtual (RV) es una intervención del dolor no farmacológica y prometedora porque es capaz no solo de distraer el dolor sino también de modularlo sumergiendo al usuario en una realidad paralela tridimensional de 360°. Se ha informado que, en niños, la RV reduce el dolor clínico y la ansiedad durante las intervenciones médicas. No obstante, se siguen investigando los efectos de la RV inmersiva sobre el dolor y la ansiedad mediante ensayos controlados aleatorios (ECA). El objetivo del presente ECA cruzado es la evaluación de los efectos de la RV sobre el umbral dedolor por presión (UDP) y el nivel de ansiedad medidos con la modified Yale Preoperative Anxiety Scale (mYPAS) en niños en un entorno experimental controlado. Metodología: Un total de setenta y dos niños (edad promedio de 10,2 (6 a 14) años) fueron asignados aleatoriamente a 24 secuencias de cuatro intervenciones (juego de RV inmersiva, vídeo de RV inmersiva, tableta electrónica: vídeo en 2D y controles: pequeña charla). Antes y después de cada intervención se evaluaron las medidas de resultados siguientes: UDP, mYPAS y frecuencia cardiaca.Resultados: Se observó un aumento significativo en el UDP durante el juego de RV (PPTdiff): 136kPa (CI 112; 161), p < 0,0001 y vídeo de RV (PPTdiff): 122kPa (CI 91; 153), p < 0,0001. Además, los niveles de ansiedad disminuyeron de forma significativa durante el juego de RV (mYPASdiff: −7 puntos (−8 a −5), p < 0,0001) y el vídeo de RV (mYPASdiff: −6 puntos (CI −7; −4), p < 0,0001). Conclusiones: La RV demostró tener unos efectos notablemente beneficiosos sobre el UDP y la ansiedad comparada con las intervenciones de control: vídeo en 2D y pequeña charla. Así, la RV inmersiva tuvo un efecto modulatorio distintivo sobre el dolor y la ansiedad en un entorno experimental adecuadamente controlado.(AU)

Background: Virtual reality (VR) is a promising non-pharmacological pain intervention because it may not only distract but also modulate pain by immersing the user in a three-dimensional 360° alternate reality. In children, VR has been reported to reduce clinical pain and anxiety during medical procedures. However, the effect of immersive VR on pain and anxiety remains to be investigated in randomized controlled trials (RCT). The aim of the present crossover RCT was to assess the effect of VR on pressure pain threshold (PPT) and anxiety level measured with the modified Yale Preoper-ative Anxiety Scale (mYPAS) in children in a controlled experimental setting. Methods: Seventy-two children (mean age 10.2 (6–14) years) were randomized to 24 sequences of four interventions (immersive VR Game, immersive VR video, tablet: 2D video and control: small talk). Outcome measures PPT, mYPAS and heart rate were assessed before and after each intervention. Results: PPT increased significantly during VR game (PPTdiff): 136 kPa (CI 112; 161), p < 0.0001 and VR Video (PPTdiff): 122 kPa (CI 91; 153), p < 0.0001. Also, anxiety levels significantly decreased during both VR game (mYPASdiff: −7 points (−8 to −5), p < 0.0001) and VR video (mYPASdiff: −6 points (CI −7; −4), p < 0.0001).Conclusions: VR had a marked beneficial effect on PPT and anxiety compared with the control interventions: 2D video and small talk. Thus, immersive VR had a distinct modulatory effect on pain and anxiety in a well-controlled experimental setting. Immersive VR was effective and feasible in children and can act as a valid tool for non-pharmacological pain and anxiety management...(AU)

Challenges in the cross-sectoral collaboration on vulnerable pregnant women: a qualitative study among Danish general practitioners.

BACKGROUND: Vulnerable pregnant women, defined as women threatened by social, psychological, or physical risk factors, need special support during pregnancy to prevent complications in pregnancy, birth, and childhood. Proper cross-sectoral collaboration in antenatal care is paramount to delivering sufficient supportive care to these women. General practitioners (GPs) often face barriers when assessing vulnerable pregnant women and may; as a result, under-identify and underreport child abuse. Little is known about how the cross-sectoral collaboration in antenatal care affects the GP's opportunities of managing vulnerable pregnant women. This study explores GPs' perceived barriers and facilitators in the antenatal care collaboration on vulnerable pregnant women and in the reporting of these women to social services. METHODS: A qualitative study with semi-structured focus group interviews among twenty GPs from the Region of Southern Denmark. A mixed inductive and deductive analytic strategy was applied, structured according to the Theoretical Domains Framework (TDF). RESULTS: Three themes emerged: I) collaborative experience, II) motivation, and III) organizational working conditions. Barriers were lacking experience, i.e. knowledge, skills, and attention to antenatal care collaboration and reporting, inadequate organizational working contexts, i.e. insufficient pathways for communication between health care and social care systems, and laws restricting feedback on the consequences of reporting. This decreased the GPs motivation, i.e. poor confidence in navigating the system, fear of breaking the patient alliance when collaborating in antenatal care and reporting with the social services. GPs motivation to collaborate and report was increased by knowing the working contexts of their collaborative partners in the antenatal care and social services system and by a strong doctor-patient relationship enabling them to describe the vulnerability to collaborators. CONCLUSIONS: GPs experience system-related barriers to collaborating and reporting on vulnerable pregnant women within the health care sector and in the interplay with the social services sector. Organizational development of cross-sectoral antenatal care collaboration should imply user involvement of all collaborative partners. Results suggest that health authorities should consider establishing accessible communication pathways between the GPs and the social services to improve options for proper cross-sectoral communication and feedback to GPs, thereby improving care trajectories of vulnerable pregnant women.

Assessing and addressing vulnerability in pregnancy: General practitioners perceived barriers and facilitators - a qualitative interview study.

BACKGROUND: Vulnerability due to low psychosocial resources increases among women in the fertile age. Undetected vulnerability in pregnancy is a major contributor to inequality in maternal and perinatal health and constitutes a risk of maternal depression, adverse birth outcomes,-i.e. preterm birth, low birth weight, and adverse outcomes in childhood such as attachment disorders. General practitioners (GPs) have a broad understanding of indicators of vulnerability in pregnancy. However, less than 25% of pregnant women with severe vulnerability are identified in Danish general practice. The aim was to explore GPs' perceived barriers and facilitators for assessing and addressing vulnerability among pregnant women. METHODS: A qualitative study with semi-structured focus group interviews with twenty GPs from urban and rural areas throughout the Region of Southern Denmark. A mixed inductive and deductive analytic strategy was applied, structured according to the Theoretical Domains Framework (TDF). RESULTS: Five themes emerged covering twelve TDF domains: (I)knowledge and attention, (II)professional confidence, (III)incentives, (IV)working conditions and (V)behavioral regulations. Prominent barriers to assessment were lack of continuity of care and trust in the doctor-patient relation. Other barriers were inattention to indicators of vulnerability, time limits, unavailable information on patients' social support needs from cross-sectoral collaborators, and lack of reimbursement for the use of extra time. Fear of damaging the doctor-patient relation, ethical dilemmas and time limits were barriers to addressing vulnerability. Facilitators were increased attention on vulnerability, professionalism and a strong and trustful doctor-patient relation. Behavioral regulations ensuring continuity of care and extra time for history taking enabled assessing and addressing vulnerability, especially when a strong doctor-patient relation was absent. CONCLUSIONS: The TDF disclosed several barriers, especially in the absence of a strong doctor-patient relation. A behavior change intervention of restructuring the organization of antenatal care in general practice might reduce the GPs' barriers to assessing and addressing vulnerability in pregnancy. The findings may serve as a guide for commissioners and policymakers of antenatal care on the GPs' support needs when providing antenatal care to vulnerable pregnant women.

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.

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.

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.

Impact of litter size, supplementary milk replacer and housing on the body composition of piglets from hyper-prolific sows at weaning.

The modern hyper-prolific sow gives birth to 17 live-born piglets on average. An alternative strategy to nurse sows and artificial rearing may be providing milk replacer while letting all the piglets stay with their dam. However, milk replacer is of lower nutritional quality than sow milk and may reduce the body fat content of piglets who use milk replacer to compensate for low suckling success due to competition at the udder. Therefore, the aim of this study was to investigate the body composition at weaning of two random sow-reared piglets per litter from 93 litters by using the deuterium oxide dilution technique. The piglets were part of large study with a 2×2×2 factorial design of either 14 or 17 piglets from day 1 (LS: LS14/LS17) with or without access to milk replacer (MILK: -MILK/+MILK) and reared by crated or loose-housed sows (HOUSING: CRATE/ LOOSE). From behavioral observations day 21 in +MILK, piglets were divided according to their frequency of drinking milk replacer and suckling (Nutrition Source). Increasing LS from 14 to 17 reduced the average daily gain from 258 to 228 g/d and body fat % from 14.4 to 12.7% (P<0.01). In a two-way interaction between LS and HOUSNG, the body fat percentage was lower (P=0.04) and the water percentage tended to be higher (P=0.07) in LS17 CRATE compared to the other treatments (i.e. LS17 LOOSE, LS14 CRATE and LOOSE). There was no effect of MILK on piglet composition day 28 (P>0.1). In +MILK, the Nutrition Source affected piglet body composition (P<0.05) as piglets with low suckling frequency (LOW) had lower body fat and higher water content compared to piglets who had high suckling frequency (SUCKLE). Unexpectedly, drinking milk replacer in addition to suckling (MIXED) did not increase piglet body fat content. Relying mainly on milk replacer (CUP) caused body fat and water contents to be intermediate to piglets with high (SUCKLE and MIXED) and low suckling frequency (LOW). In conclusion, LS had a clear impact on piglet growth and body composition at weaning. In contrast, supplementation of milk and housing had only negligible impact on litter performance. Some individual piglets that had low frequency of sow milk intake benefitted from milk supplementation. Loose housing appeared to benefit piglet body fat at weaning but this was due to a greater piglet mortality.

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.

Publisher Correction: The observation of vibrating pear-shapes in radon nuclei.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.