Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? SUMMARY ANSWER: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints ß = 0.017, 95% CI [0.009; 0.025], bifurcation points ß = 0.012, 95% CI [0.006; 0.018], crossing points ß = 0.017, 95% CI [0.008; 0.025], vessel points ß = 0.01, 95% CI [0.002; 0.008], and total vascular length ß = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV ß = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV ß = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV ß = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV ß -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV ß = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically. LIMITATION, REASONS FOR CAUTION: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered at the Dutch Trial Register (NTR6854).

TENDL-based evaluation and adjustment of p+111Cd between 1 and 100 MeV.

Proton induced reaction data are needed in the optimization of various radioisotope production routes, among others. In this work, the evaluation of proton-induced reactions on 111Cd between 1 and 100 MeV using the TALYS code system within an iterative Bayesian Monte Carlo (iBMC) framework, is presented. The method involves the simultaneous variation of a large number of nuclear reaction models included in the TALYS code system as well as their parameters. Each random TALYS calculation yields a vector of calculated values of cross section observables as well as the angular distributions, among others, which were compared with corresponding vectors of carefully selected differential experimental data for reaction channels where data were available. The random nuclear data file with the maximum likelihood function value obtained from combining the individual χ2s computed for the considered reaction channels was chosen as the parent vector and the starting point for the generation of a further set of random TALYS calculations. This was repeated multiple times until a targeted convergence of 5% was reached. The final evaluated file was compared with available experimental data from the EXFOR database as well as with the evaluations from the TENDL-2021 and JENDL5.0 libraries, and found to compare favorably.

Embryonic morphological development is delayed in pregnancies ending in a spontaneous miscarriage.

STUDY QUESTION: Is there a difference in embryonic morphological development between ongoing pregnancies and live pregnancies ending in a miscarriage? SUMMARY ANSWER: Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage compared to ongoing pregnancies. WHAT IS KNOWN ALREADY: Pregnancies ending in a miscarriage tend to have smaller embryos and slower heart rates. STUDY DESIGN, SIZE, DURATION: Between 2010 and 2018, 644 women with singleton pregnancies, in the periconception period, were enrolled in a prospective cohort study with follow up until 1 year after delivery. A miscarriage was registered as a non-viable pregnancy before 22 weeks gestational age, defined by an absent heartbeat by ultrasound for a previously reported live pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnant women with live singleton pregnancies were included and serial three-dimensional transvaginal ultrasound scans were performed. Embryonic morphological development was assessed by the Carnegie developmental stages and evaluated using virtual reality techniques. The embryonic morphology was compared to clinically used growth parameters (i.e. crown-rump length (CRL) and embryonic volume (EV)). Linear mixed models were used to evaluate the association between miscarriage and the Carnegie stages. Logistic regression with generalized estimating equations was used to calculate the odds of a miscarriage after a delay in Carnegie stages. Adjustments were made for potential confounders or covariates and include age, parity, and smoking status. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 611 ongoing pregnancies and 33 pregnancies ending in a miscarriage were included between 7 + 0 and 10 + 3 weeks gestational age, resulting in 1127 assigned Carnegie stages for evaluation. Compared to an ongoing pregnancy, a pregnancy ending in a miscarriage is associated with a lower Carnegie stage (ßCarnegie = -0.824, 95% CI -1.190; -0.458, P < 0.001). A live embryo of a pregnancy ending in a miscarriage will reach the final Carnegie stage with a delay of 4.0 days compared to an ongoing pregnancy. A pregnancy ending in a miscarriage is associated with a smaller CRL (ßCRL = -0.120, 95% CI -0.240; -0.001, P = 0.049) and EV (ßEV = -0.060, 95% CI -0.112; -0.007, P = 0.027). The delay in Carnegie stage increases the odds of a miscarriage by 1.5% per delayed Carnegie stage (ORCarnegie = 1.015, 95% CI 1.002; 1.028, P = 0.028). LIMITATIONS, REASONS FOR CAUTION: We included a relatively small number of pregnancies ending in a miscarriage from a study population that is recruited from a tertiary referral centre. Furthermore, results of genetic testing on the products of the miscarriages or information on the karyotype of the parents were not available. WIDER IMPLICATIONS OF THE FINDINGS: Embryonic morphological development, assessed by the Carnegie stages, is delayed in live pregnancies ending in a miscarriage. In the future, embryonic morphology may be used to estimate the likelihood of a pregnancy continuing to the delivery of a healthy baby. This is of crucial importance for all women but in particular for those at risk of a recurrent pregnancy loss. As part of supportive care, both women and their partners may benefit from information on the prospective outcome of the pregnancy and the timely identification of a miscarriage. STUDY FUNDING/COMPETING INTEREST(S): The work was funded by the Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Expression of risk genes linked to vitamin D receptor super-enhancer regions and their association with phenotype severity in multiple sclerosis.

Multiple sclerosis (MS) is a chronic debilitating neurological condition with a wide range of phenotype variability. A complex interplay of genetic and environmental factors contributes to disease onset and progression in MS patients. Vitamin D deficiency is a known susceptibility factor for MS, however the underlying mechanism of vitamin D-gene interactions in MS etiology is still poorly understood. Vitamin D receptor super-enhancers (VSEs) are enriched in MS risk variants and may modulate these environment-gene interactions. mRNA expression in total of 64 patients with contrasting MS severity was quantified in select genes. First, RNA-seq was performed on a discovery cohort (10 mild, 10 severe MS phenotype) and ten genes regulated by VSEs that have been linked to MS risk were analyzed. Four candidates showed a significant positive association (GRINA, PLEC, PARP10, and LRG1) in the discovery cohort and were then quantified using digital droplet PCR (ddPCR) in a validation cohort (33 mild, 11 severe MS phenotype). A significant differential expression persisted in the validation cohort for three of the VSE-MS genes: GRINA (p = 0.0138), LRG1 (p = 0.0157), and PLEC (p = 0.0391). In summary, genes regulated by VSE regions that contain known MS risk variants were shown to have differential expression based on disease severity (p<0.05). The findings implicate a role for vitamin D super-enhancers in modulating disease activity. In addition, expression levels may have some utility as prognostic biomarkers in the future.

Associations Among Parental Caregiving Quality, Cannabinoid Receptor 1 Expression-Based Polygenic Scores, and Infant-Parent Attachment: Evidence for Differential Genetic Susceptibility?

Attachment is a biological evolutionary system contributing to infant survival. When primary caregivers/parents are sensitive and responsive to their infants' needs, infants develop a sense of security. Secure infant attachment has been linked to healthy brain and organ-system development. Belsky and colleagues proposed the term differential susceptibility to describe context-dependent associations between genetic variations and behavioral outcomes as a function of parenting environments. Variations in the Cannabinoid Receptor Gene 1 (CNR1) are associated with memory, mood, and reward and connote differential susceptibility to more and less optimal parental caregiving quality in predicting children's behavioral problems. AIM: To determine if parental caregiving quality interacts with children's expression-based polygenic risk score (ePRS) for the CNR1 gene networks in the prefrontal cortex, striatum, and hippocampus in predicting the probability of attachment security and disorganized attachment. DESIGN: Prospective correlational methods examined maternal-infant pairs (n = 142) from which infants provided DNA samples at 3 months. Parental caregiving quality was assessed via the Child Adult Relationship Experiment (CARE)-index at 6 months, and attachment security via the Strange Situation Procedure at a mean age of 22 months. The CNR1 ePRSs include genes co-expressed with the CNR1 genes in the prefrontal cortex, striatum, or hippocampus, and were calculated using the effect size of the association between the individual single nucleotide polymorphisms from those genes and region-specific gene expression (GTEx). Logistic regression was employed (alpha < 0.05, two-tailed) to examine the main and interaction effects between parental caregiving quality and ePRSs in predicting attachment patterns. Interpretation of results was aided by analyses that distinguished between differential susceptibility and diathesis-stress. RESULTS: Significant interactions were observed between (1) maternal sensitivity and ePRS in the striatum in predicting attachment security, (2) maternal unresponsiveness with the ePRS in the hippocampus in predicting disorganization, and (3) maternal controlling with the ePRS in the hippocampus in predicting disorganization. CONCLUSION: These findings offer support for genetic differential susceptibility to the quality of maternal sensitivity in the context of the ePRS in the striatum. However, the significant interactions between hippocampal ePRS and maternal unresponsiveness and controlling in predicting the probability of disorganization were more suggestive of the diathesis-stress model.

Highly Elevated Prevalence of Spinobulbar Muscular Atrophy in Indigenous Communities in Canada Due to a Founder Effect.

OBJECTIVE: Spinobulbar muscular atrophy (SBMA) is an X-linked adult-onset neuromuscular disorder that causes progressive weakness and androgen insensitivity in hemizygous males. This condition is reported to be extremely rare, but has higher prevalence in certain populations due to multiple founder effects. Anecdotal observations of a higher prevalence of SBMA in patients of Indigenous descent in Saskatchewan led us to perform this study, to estimate the disease prevalence, and to attempt to identify a founder effect. METHODS: For our prevalence estimation, we identified patients with confirmed SBMA diagnosis from the Saskatoon neuromuscular clinic database for comparison with population data available from Statistics Canada. For our haplotype analysis, participants with SBMA were recruited from 2 neuromuscular clinics, as well as 5 control participants. Clinical data were collected, as well as a DNA sample using saliva kits. We performed targeted quantification of DXS1194, DXS1111, DXS135, and DXS1125 microsatellite repeats and the AR GGC repeat to attempt to identify a disease haplotype and compare it with prior studies. RESULTS: We estimate the prevalence of SBMA among persons of Indigenous descent in Saskatchewan as 14.7 per 100,000 population. Although we believe that this is an underestimate, this still appears to be the highest population prevalence for SBMA in the world. A total of 21 participants were recruited for the haplotype study, and we identified a unique haplotype that was shared among 13 participants with Indigenous ancestry. A second shared haplotype was identified in 2 participants, which may represent a second founder haplotype, but this would need to be confirmed with future studies. CONCLUSIONS: We describe a very high prevalence of SBMA in western Canadians of Indigenous descent, which appears to predominantly be due to a founder effect. This necessitates further studies of SBMA in these populations to comprehensively ascertain the disease prevalence and allow appropriate allocation of resources to support individuals living with this chronic disease.

First-trimester utero-placental (vascular) development and embryonic and fetal growth: The Rotterdam periconception cohort.

INTRODUCTION: Impaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth. METHODS: In a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex. RESULTS: PV trajectories were positively associated with CRL (ßadj = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (ßadj = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (ßadj = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (ßadj = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046). DISCUSSION: First-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth.

Surface-Layer Wind Shear and Momentum Transport From Clear-Sky to Cloudy Weather Regimes Over Land.

This study investigates how wind shear and momentum fluxes in the surface- and boundary layer vary across wind and cloud regimes. We use a 9-year-long data set from the Cabauw observatory complemented by (8.2 × 8.2 k m 2 ) daily Large Eddy Simulation (LES) hindcasts. An automated algorithm classifies observed and simulated days into different cloud regimes: (a) clear-sky days, (b) days with shallow convective clouds rooted in the surface layer, with two ranges of cloud cover, and (c) non-convective cloud days. Categorized days in observations and LES do not always match, particularly the number of non-convective cloud days are underestimated in the LES, which likes to develop convection. However, the climatology and diurnal cycle of winds for each regime are very similar in LES and observations, strengthening our confidence in LES' skill to reproduce certain clouds for certain atmospheric states. Along-wind momentum flux profiles are similar across all regimes, but large cloud cover (convective and non-convective) days have larger total momentum flux distributed over a deeper layer, with up to 30% of the surface flux still present near cloud base. The clear-sky and especially shallow cumulus regime with low cloud cover have notably larger crosswind momentum fluxes in the boundary layer. Surface-layer wind shear at daytime is smallest in the shallow cumulus regimes, having deeper boundary layers and a steady increase in surface layer wind speed during daytime. Compared to clear-sky days at a similar stability, convective cloud regimes have smaller surface-layer wind shear and larger surface friction than estimated by Monin-Obukhov Similarity Theory.

Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss.

Background: Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Method: Several MFN2-mediated functions were characterized in fibroblast cells from a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy, who harbours a novel homozygous MFN2 variant, D414V, which is found in a region of the HR1 domain of MFN2 where few pathogenic variants occur. Results: We found evidence for impairment of several MFN2-mediated functions. Consistent with reduced mitochondrial fusion, patient fibroblasts exhibited more fragmented mitochondrial networks and had reduced mtDNA copy number. Additionally, patient fibroblasts had reduced oxygen consumption, fewer mitochondrial-ER contacts, and altered lipid droplets that displayed an unusual perinuclear distribution. Conclusion: Overall, this work characterizes D414V as a novel variant in MFN2 and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

Long-term cardiometabolic disease risk in women with PCOS: a systematic review and meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with cardiometabolic disease, but recent systematic reviews and meta-analyses of longitudinal studies that quantify these associations are lacking. OBJECTIVE AND RATIONALE: Is PCOS a risk factor for cardiometabolic disease? SEARCH METHODS: We searched from inception to September 2019 in MEDLINE and EMBASE using controlled terms (e.g. MESH) and text words for PCOS and cardiometabolic outcomes, including cardiovascular disease (CVD), stroke, myocardial infarction, hypertension (HT), type 2 diabetes (T2D), metabolic syndrome and dyslipidaemia. Cohort studies and case-control studies comparing the prevalence of T2D, HT, fatal or non-fatal CVD and/or lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) between women with and without PCOS of ≥18 years of age were eligible for this systematic review and meta-analysis. Studies were eligible regardless of the degree to which they adjusted for confounders including obesity. Articles had to be written in English, German or Dutch. Intervention studies, animal studies, conference abstracts, studies with a follow-up duration less than 3 years and studies with less than 10 PCOS cases were excluded. Study selection, quality assessment (Newcastle-Ottawa Scale) and data extraction were performed by two independent researchers. OUTCOMES: Of the 5971 identified records, 23 cohort studies were included in the current systematic review. Women with PCOS had increased risks of HT (risk ratio (RR): 1.75, 95% CI 1.42 to 2.15), T2D (RR: 3.00, 95% CI 2.56 to 3.51), a higher serum concentration of TC (mean difference (MD): 7.14 95% CI 1.58 to 12.70 mg/dl), a lower serum concentration of HDL-C (MD: -2.45 95% CI -4.51 to -0.38 mg/dl) and increased risks of non-fatal cerebrovascular disease events (RR: 1.41, 95% CI 1.02 to 1.94) compared to women without PCOS. No differences were found for LDL-C (MD: 3.32 95% CI -4.11 to 10.75 mg/dl), TG (MD 18.53 95% CI -0.58 to 37.64 mg/dl) or coronary disease events (RR: 1.78, 95% CI 0.99 to 3.23). No meta-analyses could be performed for fatal CVD events due to the paucity of mortality data. WIDER IMPLICATIONS: Women with PCOS are at increased risk of cardiometabolic disease. This review quantifies this risk, which is important for clinicians to inform patients and to take into account in the cardiovascular risk assessment of women with PCOS. Future clinical trials are needed to assess the ability of cardiometabolic screening and management in women with PCOS to reduce future CVD morbidity.

First trimester anomaly scan using virtual reality (VR FETUS study): study protocol for a randomized clinical trial.

BACKGROUND: In recent years it has become clear that fetal anomalies can already be detected at the end of the first trimester of pregnancy by two-dimensional (2D) ultrasound. This is why increasingly in developed countries the first trimester anomaly scan is being offered as part of standard care. We have developed a Virtual Reality (VR) approach to improve the diagnostic abilities of 2D ultrasound. Three-dimensional (3D) ultrasound datasets are used in VR assessment, enabling real depth perception and unique interaction. The aim of this study is to investigate whether first trimester 3D VR ultrasound is of additional value in terms of diagnostic accuracy for the detection of fetal anomalies. Health-related quality of life, cost-effectiveness and also the perspective of both patient and ultrasonographer on the 3D VR modality will be studied. METHODS: Women in the first trimester of a high risk pregnancy for a fetus with a congenital anomaly are eligible for inclusion. This is a randomized controlled trial with two intervention arms. The control group receives 'care as usual': a second trimester 2D advanced ultrasound examination. The intervention group will undergo an additional first trimester 2D and 3D VR ultrasound examination. Following each examination participants will fill in validated questionnaires evaluating their quality of life and healthcare related expenses. Participants' and ultrasonographers' perspectives on the 3D VR ultrasound will be surveyed. The primary outcome will be the detection of fetal anomalies. The additional first trimester 3D VR ultrasound examination will be compared to 'care as usual'. Neonatal or histopathological examinations are considered the gold standard for the detection of congenital anomalies. To reach statistical significance and 80% power with a detection rate of 65% for second trimester ultrasound examination and 70% for the combined detection of first trimester 3D VR and second trimester ultrasound examination, a sample size of 2800 participants is needed. DISCUSSION: First trimester 3D VR detection of fetal anomalies may improve patients' quality of life through reassurance or earlier identification of malformations. Results of this study will provide policymakers and healthcare professionals with the highest level of evidence for cost-effectiveness of first trimester ultrasound using a 3D VR approach. TRIAL REGISTRATION: Dutch Trial Registration number NTR6309 , date of registration 26 January 2017.

Parenting Interacts With Plasticity Genes in Predicting Behavioral Outcomes in Preschoolers.

BACKGROUND: Public health and pediatric nurses typically focus on supporting parenting to reduce the likelihood of children's behavioral problems. Studies have identified interactions between early exposures to stress in caregiving and child genotype in predicting children's behavioral problems, such that certain genotypes connote greater differential susceptibility or plasticity to environmental stressors. We sought to uncover the interaction between observational measures of parent-child relationship quality and genotype in predicting early-onset behavioral problems in 24-month-olds, using prospective methods. METHODS: We conducted a secondary analysis of data collected on a subsample of 176 women and their infants enrolled during pregnancy in the ongoing Alberta Pregnancy Outcomes and Nutrition (APrON) cohort study. Inclusion criteria required mothers to be ≥18 years of age, English speaking and ≤22 weeks gestational age at enrollment. Genetic data were obtained from blood leukocytes and buccal epithelial cell samples, collected from infants at three months of age. For each child, the presence of plasticity alleles was determined for BDNF, CNR1, DRD2/ANKK1, DRD4, DAT1, 5-HTTLPR, and MAOA and an overall index was calculated to summarize the number of plasticity alleles present. Observational assessments of parent-child relationship quality (sensitivity, controlling, and unresponsiveness) were conducted at six months of age. Children's internalizing (e.g., emotionally reactive, anxious/depressed, somatic complaint, withdrawn) and externalizing (e.g., aggression, inattention) behaviors were assessed at 24 months of age. After extracting genetic data, a maximum likelihood method for regressions was employed with Akaike Information Criterion (AIC) for model selection. RESULTS: When parents were less responsive and children possessed more plasticity alleles, children were more likely to be emotionally reactive, anxious/depressed, report somatic complaints, and withdrawn, while when parents were less responsive and children possessed fewer plasticity alleles, children were less likely to display these internalizing behaviors, in a differentially susceptible manner. Furthermore, when parents were more responsive, and children possessed more plasticity alleles, children were less likely to display internalizing behaviors (P = 0.034). Similarly, children who possessed either the CNR1-A plasticity allele (P = 0.010) or DAT1 9-repeat plasticity allele (P = 0.036) and experienced more/less parental control displayed more/fewer externalizing problems, respectively, in a differentially susceptible manner. CONCLUSIONS: The plasticity index score interacted with parental unresponsiveness in predicting anxiety and depressive behavioral problems in children, while individual genetic variants interacted with parental controlling behavior in predicting aggression and inattention in children, suggestive of differential susceptibility to caregiving. Especially in the context of nursing interventions designed to support childrearing and children's development, nurses need to be aware of the interactions between child genotype and parenting in understanding how well interventions will work in promoting optimal child behavior.

CCL22 is a biomarker of cartilage injury and plays a functional role in chondrocyte apoptosis.

BACKGROUND: Osteoarthritis (OA) is one of the leading causes of disability worldwide. Previous history of knee injury is a significant risk factor for OA. It has been established that low-level chronic inflammation plays a pivotal role in the onset and pathogenesis of OA. The primary aim of this research was to determine if a history of knee joint injury is associated with systemic inflammation. A secondary aim was to determine if systemic inflammation is related to knee pain and joint structure. METHODS: Differences in serum cytokine association networks, knee joint structural changes (MRI), and self-reported pain (i.e., Knee Injury and Osteoarthritis Outcome Score Pain subscale, KOOSPAIN and Intermittent and Constant Osteoarthritis Pain score, ICOAP) between individuals who had sustained a youth (aged 15-26 years) sport-related knee injury 3-10 years previously and age- and sex-matched controls were examined. Proteins of interest were also examined in an OA rat model. RESULTS: Cytokine association networks were found to differ significantly between study groups, yet no significant associations were found between networks and KOOSPAIN or MRI-defined OA. A group of cytokines (MCP1/CCL2, CCL22 and TNFα) were differentially associated with other cytokines between study groups. In a pre-clinical rat OA model, serum CCL22 levels were associated with pain (r = 0.255, p = 0.045) and structural changes to the cartilage. CCL22 expression was also observed in human OA cartilage and furthermore, CCL22 induced apoptosis of isolated human chondrocytes. DISCUSSION: These results suggest that CCL22 may be an early factor in the onset/pathogenic process of cartilage degeneration and/or related to pain OA.

Molecular Adaptations for Sensing and Securing Prey and Insight into Amniote Genome Diversity from the Garter Snake Genome.

Colubridae represents the most phenotypically diverse and speciose family of snakes, yet no well-assembled and annotated genome exists for this lineage. Here, we report and analyze the genome of the garter snake, Thamnophis sirtalis, a colubrid snake that is an important model species for research in evolutionary biology, physiology, genomics, behavior, and the evolution of toxin resistance. Using the garter snake genome, we show how snakes have evolved numerous adaptations for sensing and securing prey, and identify features of snake genome structure that provide insight into the evolution of amniote genomes. Analyses of the garter snake and other squamate reptile genomes highlight shifts in repeat element abundance and expansion within snakes, uncover evidence of genes under positive selection, and provide revised neutral substitution rate estimates for squamates. Our identification of Z and W sex chromosome-specific scaffolds provides evidence for multiple origins of sex chromosome systems in snakes and demonstrates the value of this genome for studying sex chromosome evolution. Analysis of gene duplication and loss in visual and olfactory gene families supports a dim-light ancestral condition in snakes and indicates that olfactory receptor repertoires underwent an expansion early in snake evolution. Additionally, we provide some of the first links between secreted venom proteins, the genes that encode them, and their evolutionary origins in a rear-fanged colubrid snake, together with new genomic insight into the coevolutionary arms race between garter snakes and highly toxic newt prey that led to toxin resistance in garter snakes.

Three-dimensional ultrasonography of the breast; An adequate replacement for MRI in neoadjuvant chemotherapy tumour response evaluation? - RESPONDER trial.

BACKGROUND: Accurate measurement of tumour response during and after neoadjuvant chemotherapy (NAC) is important and may influence treatment decisions in invasive breast cancer patients. Breast MRI forms the gold standard but is more burdensome, time consuming and costly. In this study response measurement was done with 3-D ultrasound by Automated Breast Volume Scanner (ABVS) and compared to breast MRI. Moreover, patient satisfaction with both techniques was compared. METHODS AND MATERIALS: A single-institution, prospective observational pilot study evaluating tumour response by ABVS in addition to breast MRI (standard care) was performed in 25 invasive breast cancer patients receiving NAC. Tumour response was evaluated comparing longest tumour diameters as well as tumour volumes at predefined time points using Bland-Altman analysis. Volume measurements for breast MRI were obtained using a fully immersive virtual reality system (a Barco I-Space) and V-Scope software. Same software was used to obtain ABVS volume measurements using an in-house developed desktop VR system. Inter- and intra-observer agreement was evaluated by Intraclass Correlation Coefficient (ICC). RESULTS: Twenty-five patients were eligible for baseline measurement, 20 for a mid-NAC response evaluation, and five for a post-NAC response evaluation. MRI and ABVS showed absolute concordance in 73% of patients for the mid-NAC evaluation, with a 'good' correlation for the difference in longest diameter measurement (ICC 0.73, p < 0.01) as compared to baseline assessment. Concerning difference in volume measurement in the mid-NAC response evaluation showed a 'fair' correlation (ICC 0.52, p < 0.01) and in the post-NAC response evaluation an 'excellent' correlation (ICC 0.98, p < 0.01). 'Excellent' inter- and intra-observer agreement was found (ICC 0.88, p < 0.01) with comparable limits of agreement (LOA) for observer 1 and 2 in both diameter and volume measurement. Patient satisfaction was higher for ABVS compared to breast MRI, 93% versus 12% respectively. CONCLUSION: ABVS showed 'good' correlation with MRI tumour response evaluation in breast cancer patients during NAC with 'excellent' inter- and intra-observer agreement. ABVS has patients' preference over breast MRI and could be considered as alternative to breast MRI, in case results on an on-going prospective trial confirm these results (NTR6799).

Breast and Tumour Volume Measurements in Breast Cancer Patients Using 3-D Automated Breast Volume Scanner Images.

BACKGROUND: The resection volume in relation to the breast volume is known to influence cosmetic outcome following breast-conserving therapy. It was hypothesised that three-dimensional ultrasonography (3-D US) could be used to preoperatively assess breast and tumour volume and show high association with histopathological measurements. METHODS: Breast volume by the 3D-US was compared to the water displacement method (WDM), mastectomy specimen weight, 3-D MRI and three different calculations for breast volume on mammography. Tumour volume by the 3-D US was compared to the histopathological tumour volume and 3-D MRI. Relatedness was based on the intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (95% CI). Bland-Altman plots were used to graphically display the agreement for the different assessment techniques. All measurements were performed by one observer. RESULTS: A total of 36 patients were included, 20 and 23 for the evaluation of breast and tumour volume (ductal invasive carcinomas), respectively. 3-D US breast volume showed 'excellent' association with WDM, ICC 0.92 [95% CI (0.80-0.97)]. 3-D US tumour volume showed a 'excellent' association with histopathological tumour volume, ICC 0.78 [95% CI (0.55-0.91)]. Bland-Altman plots showed an increased overestimation in lager tumour volumes measured by 3-D MRI compared to histopathological volume. CONCLUSIONS: 3-D US showed a high association with gold standard WDM for the preoperative assessment of breast volume and the histopathological measurement of tumour volume. 3-D US is an patient-friendly preoperative available technique to calculate both breast volume and tumour volume. Volume measurements are promising in outcome prediction of intended breast-conserving treatment.

New imaging markers for preconceptional and first-trimester utero-placental vascularization.

INTRODUCTION: The availability of imaging makers of early placental circulation development is limited. This study aims to develop a feasible and reliable method to assess preconceptional and early first-trimester utero-placental vascular volumes using three-dimensional power Doppler (3D PD) ultrasound on two different Virtual Reality (VR) systems. METHODS: 3D PD ultrasound images of the uterine and placental vasculature were obtained in 35 women, either preconceptionally (n = 5), or during pregnancy at 7 (n = 10), 9 (n = 10) or 11 (n = 10) weeks of gestation. Preconceptional uterine vascular volume (UVV), first-trimester placental vascular volume (PVV) and embryonic vascular volume (EVV) were measured by two observers on two VR systems, i.e., a Barco I-Space and VR desktop. Intra- and inter-observer agreement and intersystem agreement were assessed by intra-class correlation coefficients (ICC) and absolute and relative differences. RESULTS: Uterine-, embryonic- and placental vascular volume measurements showed good to excellent intra- and inter-observer agreement and inter-system reproducibility with most ICC above 0.80 and relative differences of less than 20% preconceptionally and almost throughout the entire gestational age range. Inter-observer agreement of PVV at 11 weeks gestation was suboptimal (ICC 0.69, relative difference 50.1%). DISCUSSION: Preconceptional and first-trimester 3D PD ultrasound utero-placental and embryonic vascular volume measurements using VR are feasible and reliable. Longitudinal cohort studies with repeated measurements are needed to further validate this and assess their value as new imaging markers for placental vascular development and ultimately for the prediction of placenta-related pregnancy complications.

Allele Age Under Non-Classical Assumptions is Clarified by an Exact Computational Markov Chain Approach.

Determination of the age of an allele based on its population frequency is a well-studied problem in population genetics, for which a variety of approximations have been proposed. We present a new result that, surprisingly, allows the expectation and variance of allele age to be computed exactly (within machine precision) for any finite absorbing Markov chain model in a matter of seconds. This approach makes none of the classical assumptions (e.g., weak selection, reversibility, infinite sites), exploits modern sparse linear algebra techniques, integrates over all sample paths, and is rapidly computable for Wright-Fisher populations up to N e = 100,000. With this approach, we study the joint effect of recurrent mutation, dominance, and selection, and demonstrate new examples of "selective strolls" where the classical symmetry of allele age with respect to selection is violated by weakly selected alleles that are older than neutral alleles at the same frequency. We also show evidence for a strong age imbalance, where rare deleterious alleles are expected to be substantially older than advantageous alleles observed at the same frequency when population-scaled mutation rates are large. These results highlight the under-appreciated utility of computational methods for the direct analysis of Markov chain models in population genetics.

TUmor-volume to breast-volume RAtio for improving COSmetic results in breast cancer patients (TURACOS); a randomized controlled trial.

BACKGROUND: Cosmetic result following breast conserving surgery (BCS) for cancer influences quality of life and psychosocial functioning in breast cancer patients. A preoperative prediction of expected cosmetic result following BCS is not (yet) standard clinical practice and therefore the choice for either mastectomy or BCS is still subjective. Recently, we showed that tumour volume to breast volume ratio as well as tumour location in the breast are independent predictors of superior cosmetic result following BCS. Implementation of a prediction model including both factors, has not been studied in a prospective manner. This study aims to improve cosmetic outcome by implementation of a prediction model in the treatment decision making for breast cancer patients opting for BCS. METHODS/DESIGN: Multicentre, single-blinded, randomized controlled trial comparing standard preoperative work-up to a preoperative work-up with addition of the prediction model. Tumour volume to breast volume ratio and tumour location in the breast will be used to predict cosmetic outcome in invasive breast cancer patients opting for BCS. Three dimensional (3D)-ultrasonography will be used to measure the tumour volume to breast volume ratio needed for the prediction model. Sample size was estimated based on a 14% improvement in incidence of superior cosmetic result one year after BCS (71% in the control group versus 85% in the intervention group). Primarily cosmetic outcome will be evaluated by a 6-member independent panel. Secondary endpoints include; (1) patient reported outcome measured by BREAST-Q, EORTC-QLQ-C30/BR23 and EQ-5D-5 L (2) cosmetic outcome as assessed through the BCCT.core software, (3) radiation-induced reaction (4) surgical treatment performed, (5) pathological result and (6) cost-effectiveness. Follow-up data will be collected for 3 years after surgery or finishing radiotherapy. DISCUSSION: This randomized controlled trial examines the value of a preoperative prediction model for the treatment-decision making. It aims for a superior cosmetic result in breast cancer patients opting for BCS. We expect improvement of patients' quality of life and psychosocial functioning in a cost-effective way. TRIAL REGISTRATION: Prospectively registered, February 17th 2015, at 'Nederlands Trialregister - NTR4997 '.

Wright-Fisher exact solver (WFES): scalable analysis of population genetic models without simulation or diffusion theory.

Motivation: The simplifying assumptions that are used widely in theoretical population genetics may not always be appropriate for empirical population genetics. General computational approaches that do not require the assumptions of classical theory are therefore quite desirable. One such general approach is provided by the theory of absorbing Markov chains, which can be used to obtain exact results by directly analyzing population genetic Markov models, such as the classic bi-allelic Wright-Fisher model. Although these approaches are sometimes used, they are usually forgone in favor of simulation methods, due to the perception that they are too computationally burdensome. Here we show that, surprisingly, direct analysis of virtually any Markov chain model in population genetics can be made quite efficient by exploiting transition matrix sparsity and by solving restricted systems of linear equations, allowing a wide variety of exact calculations (within machine precision) to be easily and rapidly made on modern workstation computers. Results: We introduce Wright-Fisher Exact Solver (WFES), a fast and scalable method for direct analysis of Markov chain models in population genetics. WFES can rapidly solve for both long-term and transient behaviours including fixation and extinction probabilities, expected times to fixation or extinction, sojourn times, expected allele age and variance, and others. Our implementation requires only seconds to minutes of runtime on modern workstations and scales to biological population sizes ranging from humans to model organisms. Availability and Implementation: The code is available at https://github.com/dekoning-lab/wfes. Contact: jason.dekoning@ucalgary.ca. Supplementary information: Supplementary data are available at Bioinformatics online.