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Free sialic acid storage disorder (FSASD) is a rare, autosomal recessive, neurodegenerative disorder caused by biallelic mutations in SLC17A5, encoding the lysosomal transmembrane sialic acid exporter, SLC17A5. Defects in SLC17A5 lead to lysosomal accumulation of free sialic acid and other acid hexoses. The clinical spectrum of FSASD ranges from mild (Salla disease) to severe infantile forms. The pathobiology underlying FSASD remains elusive. In this study, two induced pluripotent stem cell (iPSC) lines were generated from a mild and an intermediate FSASD patient and characterized to provide much-needed additional models for basic and translational studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Aims: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data., Methods: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling., Results: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01)., Conclusions: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Road traffic crashes (RTC) are a leading cause of mortality and morbidity in young people. Severe mental health and behavioural conditions increase the likelihood of RTC, as do a range of driving-risk activities., Method: We used data from the Raine Study, a prebirth cohort from Perth, Australia, to assess the relationship between measures of common mental health or behavioural conditions (Child Behavior Checklist Internalising and Externalising scores) at age 17 and subsequent RTC by 27 years, controlling for substance use and driving-risk activities., Results: By 27 years of age, of 937 participants, 386 (41.2%) reported zero crashes and 551 (58.8%) reported ≥1 crashes. In the baseline Poisson model, increased Externalising scores (eg, aggression and delinquency) were associated with increased RTC (incidence rate ratio (IRR)=1.02, 95% CI 1.01 to 1.02): increased Internalising scores (eg, anxiety and depression) were associated with fewer RTC (IRR=0.99, 95% CI 0.98 to 1.00). In the fully adjusted model, the mental health measures were not significant (Externalising IRR=1.01, 95% CI 0.99 to 1.02: Internalising IRR=0.99, 95% CI 0.99 to 1.00). Risky driver activities, such as falling asleep while driving (IRR=1.34), more frequent use of a hands-free telephone (IRR=1.35) and more frequent hostility towards other drivers (IRR=1.30) increased the rate of RTC., Conclusion: Measures of mental health scores at age 17 were not predictive of subsequent RTC, after adjusting for measures of driving-risk activities. We need to better understand the determinants of externalising and risky driving behaviours if we are to address the increased risk of RTC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A second peak of inhibitors has been reported in patients with severe hemophilia A (HA) aged >50 years in the United Kingdom. The reason for this suggested breakdown of tolerance in the aging population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on hemophilia B (HB) have ever been reported., Aim: The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years., Methods: A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE hemophilia treatment center., Results: Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40-49), 1.25 (age 50-59), and 1.45 (age 60 + ). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 [age 40-49], 6.59 [age 50-59], and 4.69 [age 60 + ]) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with HB were reported., Conclusion: Our data do not identify a second peak of inhibitor development in older patients with hemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at a higher age., Competing Interests: J.A. reports research grants from Bayer, CSL Behring, Shire/Takeda, SOBI; consulting fees from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI; honoraria for lectures, presentations, manuscript writing from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI; participation on a DSMB or Advisory Board from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI. C.A. reports honoraria for lectures, presentations, manuscript writing from Bayer, CSL Behring, Novo Nordisk, Shire/Takeda, SOBI; support for attending meetings from SOBI. M.C. reports consulting fees from Bayer, CSL Behring, Novo Nordisk, Roche, SOBI; honoraria for lectures, presentations, manuscript writing from Bayer, CSL Behring, Novo Nordisk, Roche, SOBI; support for attending meetings from Bayer, CSL Behring, Novo Nordisk, Pfizer, Roche, SOBI; participation on a DSMB or Advisory Board from Bayer, CSL Behring, Novo Nordisk, Roche, SOBI. RdO reports consulting fees from Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI, Spark; honoraria for lectures, presentations, manuscript writing from Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI, Spark; support for attending meetings from Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI, Spark. GD reports consulting fees from Novo Nordisk, Roche; honoraria for lectures, presentations, manuscript writing from Novo Nordisk, Pfizer, Roche, Shire/Takeda. P.F. reports support for attending meetings from SOBI. C.H. reports honoraria for lectures, presentations, manuscript writing from Bayer. P.A.H. reports honoraria for lectures, presentations, manuscript writing from Bayer, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI; support for attending meetings from Bayer, Octapharma. G.K. reports research grants from Bayer, BioMarin, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis; consulting fees from ASC Therapeutics, Bayer, Pfizer, Roche, Sanofi-Aventis; honoraria for lectures, presentations, manuscript writing from Bayer, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Shire/Takeda, Spark; participation on a DSMB or Advisory Board from Bayer, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Shire/Takeda, UniQure. R.K. reports research grants from Bayer, Leo; consulting fees from Bayer, Biomarin, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI; honoraria for lectures, presentations, manuscript writing from Bayer, Biomarin, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, SOBI. M.E.M. reports consulting fees from Bayer, Biomarin, Catalyst, CSL Behring, Grifols, Kedrion, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Shire/Takeda, Sobi; honoraria for lectures, presentations, manuscript writing from Bayer, Biomarin, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Roche, Shire/Takeda, SOBI, Spark; support for attending meetings from Bayer, Novo Nordisk, Roche, SOBI. NM reports honoraria for lectures, presentations, manuscript writing from Bayer, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI; support for attending meetings from Novo Nordisk, Octapharma, Shire/Takeda, SOBI; participation on a DSMB or Advisory Board from Bayer, Novo Nordisk, SOBI. R.N. reports honoraria for lectures, presentations, manuscript writing from CSL Behring, Novo Nordisk, Octapharma, Roche, Shire/Takeda, SOBI; support for attending meetings from Octapharma, Roche; participation on a DSMB or Advisory Board from Bayer, Pfizer, Shire/Takeda. I.P. reports research grants from CSL Behring; consulting fees from Bayer, CSL Behring, Novo Nordisk, Pfizer, Roche, Shire/Takeda; honoraria for lectures, presentations, manuscript writing from Bayer, CSL Behring, Novo Nordisk, Pfizer, Shire/Takeda; participation on a DSMB or Advisory Board from Roche. R.C.T. reports consulting fees from Bayer; participation on a DSMB or Advisory Board from Roche. All other authors have no conflict of interest to declare., (Thieme. All rights reserved.)

Objectives: There is limited evidence on the impact of parental mental health problems on offspring's educational outcomes. We investigated the impact of maternal anxiety and depressive symptoms, as well as paternal emotional problems on the educational outcomes of their adolescent and young adult offspring., Methods: We used data from a longitudinal birth cohort recruited between 1989 and 1991 in Australia (the Raine Study). The Depression, Anxiety and Stress Scale was used to assess maternal depressive and anxiety symptoms, and a self-reported question was used to measure paternal mental health problems. Both were assessed when the offspring was aged 10 years. Outcomes included offspring's self-reported education attainment-not completing year 10 at age 17, not attending tertiary education at ages 17 and 22 and primary caregiver's reports of offspring's academic performance at age 17., Results: A total of 1033, 1307 and 1364 parent-offspring pairs were included in the final analysis exploring the association between parental mental health problems and offspring's academic performance at school, completing year 10 and attending tertiary education, respectively. After adjusting for potential confounders, the offspring of mothers with anxiety symptoms were 3.42 times more likely than the offspring of mothers without anxiety symptoms to have poor or below-average academic performance (odds ratio = 3.42; 95% confidence interval = [1.31, 8.92]) and more than 2 times more likely to not attend tertiary education (odds ratio = 2.55; 95% confidence interval = [1.10, 5.5.88]) and not to have completed year 10 (odds ratio = 2.13; 95% confidence interval = [1.04, 4.33]). We found no significant associations between maternal depressive symptoms or paternal emotional problems and offspring educational attainment., Conclusion: Maternal anxiety symptoms, but not depression and paternal emotional problems, are associated with poor educational attainment and achievement in adolescent offspring. The findings highlight that efforts to improve the outcomes of offspring of mothers with anxiety could focus on educational attainment.

Globally, the availability and formulations for the administration of cannabis are changing with decriminalization or legalization of recreational use in some jurisdictions, and the prescription of cannabis also occurring. These changes are likely to affect the prevalence of use, including by women of childbearing age. The effects of in utero and infant alcohol and tobacco exposure are well-documented, but the outcomes of cannabis exposure are less certain. The content of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis has progressively increased over several decades. This review explores the limited knowledge surrounding the epidemiology of gestational and postnatal cannabis exposure and implications for the mother-placenta-fetus/neonate triad. We examine cannabis' effects from antenatal and lactation exposure on (a) pregnancy and perinatal outcomes, (b) placental health, and (c) longer term cardiometabolic and neurodevelopmental risks and outcomes. Though definitive outcomes are lacking, gestational cannabis has been associated with increased risk of other substance use during pregnancy; impaired placental blood flow; increased risk of small for gestational age births; and associated complications. Childhood and adolescent outcomes are sparsely assessed, with suggested outcomes including increased risk of depression and attention-deficit hyperactivity disorder. Cardiometabolic implications of gestational cannabis use may include maternal fatty liver, obesity, insulin resistance, and increased risk of gestational diabetes mellitus (GDM), with potential consequences for the fetus. Clinical implications for pediatric practice were explored in a bid to understand any potential risk or impact on child health and development.

Apolipoprotein E (apoE) is a major lipid carrier in the brain and closely associated with the pathogenesis of Alzheimer's disease (AD). Here, we describe a protocol for efficient knockout of APOE in human induced pluripotent stem cells (iPSCs) using the CRISPR-Cas9 system. We obtain homozygous APOE knockout ( APOE -/- ) iPSCs and further validate the deficiency of apoE in iPSC-derived cerebral organoids. APOE -/- cerebral organoids can serve as a useful tool to study apoE functions and apoE-related pathogenic mechanisms in AD. For complete details on the use and execution of this protocol, please refer to Zhao et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: Epidemiological data indicate that paternal and maternal mental health difficulties are predictors of conduct disorder (CD) and oppositional defiant disorder (ODD) in offspring. We tested the association between maternal anxiety and depressive symptoms and paternal emotional problems with CD and ODD symptoms in adolescent offspring aged 17., Methods: Data was from the Raine Study, a birth cohort study based in Western Australia. Offspring CD and ODD symptoms at age 17 years were measured using the DSM-oriented scales of the Child Behavior Checklist (CBCL). Depression, Anxiety, and Stress Scale (DASS) was used to assess maternal depressive and anxiety symptoms, and a self-reported questionnaire measured paternal emotional problems when the offspring was 10 years. Negative binomial regression model was used to explore associations., Results: Adjusting for potential confounding factors, we found an increased risk of CD symptoms in the offspring of mothers with anxiety [RR = 1.76 (95%CI; 1.08-2.86)], depressive [RR = 1.40 (95%CI; 1.01-1.95)], and comorbid anxiety and depressive symptoms [RR = 2.24 (95%CI 1.35-3.72)]. We also found an increased risk of ODD symptoms in offspring of mothers with depressive [RR = 1.24 (95%CI 1.02-1.52)], but not anxiety symptoms [RR = 1.23 (95%CI 0.92-1.67)]. No associations were seen with paternal emotional problems., Conclusion: Our study showed that adolescents whose mothers reported anxiety, depressive, and comorbid anxiety and depressive symptoms had a higher risk of CD and ODD symptoms at age 17. The findings have implications for preventive strategies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There are limited studies on the risk of depressive symptoms in adolescent offspring exposed to parental mental health problems in middle childhood., Aim: We investigated the association between parental mental health problems, particularly paternal emotional problems and maternal symptoms of anxiety and depression, and the risk of depressive symptoms in adolescent offspring aged 17., Methods: The study included 995 parent-offspring pairs from the 1989-91 birth cohort (the Raine Study) in Western Australia. Log-binomial regression was used to assess the associations., Results: An increased risk of depression symptoms was observed in the adolescent offspring of mothers with depressive [RR 1.45, 95% CI 1.13-1.86] as well as anxiety symptoms [RR 1.43, 95% CI 1.09-1.87].Compared to those non-exposed, offspring whose mothers reported comorbid anxiety and depressive symptoms were more likely to have developed depressive symptoms by late adolescence [RR 1.63, 95%CI 1.11-2.38]. An increased risk of depressive symptoms was also seen in the offspring of fathers with emotional problems [RR 1.29, 95%CI 1.01-1.53]., Conclusion: Our findings suggest an increased risk of depressive symptoms in the adolescent offspring of parents with mental health problems, specifically paternal emotional problems (29%) and maternal anxiety (43%), depression (45%), as well as comorbid anxiety and depressive symptoms (63%).

Background: While previous studies have suggested that maternal anxiety and depressive symptoms are associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in their offspring in early and late childhood, studies exploring the risk in late adolescence are however lacking. This study aims to examine the association between maternal anxiety and depressive symptoms and the risk of ADHD symptoms in late adolescence (at age 17)., Methods: We used data from the Raine Study. Maternal depressive and anxiety symptoms were measured when the child was 10 years of age using the Depression, Anxiety, and Stress Scale (DASS). Offspring ADHD symptoms at age 17 were assessed using the DSM-oriented scales of the child behavior checklist (CBCL). Log-binomial regression was used to explore the associations., Results: We found an increased risk of ADHD symptoms in offspring of mothers with comorbid anxiety and depressive symptoms when compared with offspring of mothers with no symptoms [RR 5.60 (95%CI 3.02-10.37)]. There was a nearly three-fold increase in the risk of ADHD symptoms in offspring of mothers with increased anxiety symptoms compared with offspring of mothers who were in the normal range [RR 2.84 (95%CI 1.18-6.83)]. No association was observed with maternal depressive symptoms., Conclusion: This study found an increased risk of ADHD symptoms in the offspring of mothers with anxiety as well as comorbid anxiety and depressive symptoms but not among the offspring of mothers with depressive symptoms. Early screening and intervention for ADHD symptoms in offspring with maternal anxiety and comorbid anxiety and depressive symptoms are warranted., (Copyright © 2021. Published by Elsevier B.V.)

Epidemiological studies indicate that children of parents with mental health problems are at an increased risk of developing anxiety disorders. Few studies have investigated this relationship in young adults. Participants were from the Raine Study, which is a multi-generational birth cohort study in Australia. Maternal anxiety and depression in late childhood were assessed using the Depression, Anxiety, and Stress Scale (DASS-42), and paternal lifetime mental health problems were assessed using a self-reported questionnaire. The short form of DASS-42 (DASS-21) was used to assess anxiety symptoms among offspring at age 20. Negative binomial regression model was used to quantify the association. Data were available for 1,220 mother-offspring and 1,190 father-offspring pairs. After adjusting for potential confounders, we found an increased risk of anxiety in young adult offspring exposed to maternal anxiety in late childhood and paternal lifetime mental health problems. However, we observed no increased risks of anxiety in offspring exposed to maternal depressive symptoms. Our sensitivity analysis based on the log-binomial model (binary outcome) as well as the linear model (log-transformed data) confirmed the robustness of the main results. Our findings suggest there can be value to consider and apply targeted screening and intervention programs of anxiety in the young adult offspring with parental mental health problems., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Persistently impaired culprit artery flow (

Objective: Pain management in persons with mild to moderate dementia poses unique challenges because of altered pain modulation and the tendency of some individuals to perseverate. We aimed to test the impact of an e-learning module about pain in communicative people with dementia on third-year medical students who had or had not completed an experiential geriatrics course., Design: Analysis of pre- to postlearning changes and comparison of the same across the student group., Setting: University of Pittsburgh School of Medicine and Saint Louis University School of Medicine., Subjects: One hundred four University of Pittsburgh and 57 Saint Louis University medical students., Methods: University of Pittsburgh students were randomized to view either the pain and dementia module or a control module on pain during a five-day geriatrics course. Saint Louis University students were asked to complete either of the two modules without the context of a geriatrics course. A 10-item multiple choice knowledge test and three-item attitudes and confidence questionnaires were administered before viewing the module and up to seven days later., Results: Knowledge increase was significantly greater among students who viewed the dementia module while participating in the geriatrics course than among students who viewed the module without engaging in the course (P < 0.001). The modules did not improve attitudes in any group, while student confidence improved in all groups., Conclusions: Medical students exposed to e-learning or experiential learning demonstrated improved confidence in evaluating and managing pain in patients with dementia. Those exposed to both educational methods also significantly improved their knowledge., (Published by Oxford University Press on behalf of the American Academy of Pain Medicine 2020. This work is written by US Government employees and is in the public domain in the US.)

Background:  Genetic testing for pedigree accuracy is critical for managing genetic diversity in North American (NA) yak ( Bos grunniens ), a population expanded mostly from imported zoological park specimens.  DNA testing also enhances species conservation by identifying recent B. taurus F1 hybrid ancestors (within three generations).  Biallelic single nucleotide polymorphisms (SNPs) can accomplish either task, but increases the marker count and costs necessary to achieve both.  Our aim was to identify novel, multifunctional, triallelic yak SNPs (tySNPs), with each having two alleles for yak parentage testing, and a third allele for identifying recent cattle introgression.  Methods:   Genome sequences were aligned to the cattle UMD3.1 assembly and SNPs were screened for 1) heterozygosity in a NA and a Chinese yak, 2) a third allele at high frequency in cattle, and 3) flanking sequences conserved in both species.  Subsequently, tySNPs were filtered for unique alignment to the haplotype-resolved F1 yak assembly.  Allele frequencies were estimated in a subset of 87 tySNPs by genotyping 170 NA yak. Results:   We identified 610 autosomal tySNPs, distributed in 441 clusters with 5 Mb average genome spacing.  The average NA yak minor allele frequency was high (0.296), while average introgressed cattle alleles were low (0.004).  In simulations with tySNPs, 28 were sufficient for globally-unique animal identification (P I =5.81x10 -12 ), 87 were able to exclude 19 random bulls from parentage at the 99% level without using the dam's genotype (P E =5.3x10 -4 ), and 87 were able to detect F1 hybridization events after three generations of yak backcrosses (1/16th B. taurus germplasm). Conclusions :  Identifying animals, determining parentage and detecting recent hybridization events was efficient with as few as 87 tySNPs.  A similar triallelic approach could be used with other bottlenecked Bos species that hybridize with cattle, such as NA plains bison ( B. bison )., Competing Interests: Competing interests: The authors declare the following interest: co-authors RGT, JQ, and VB are full-time employees at Neogen Genomics, a company that provides agrigenomic and veterinary diagnostic services. There are no patents to declare. There is a genotyping product offered based on the methodology described in this publication. These interests to not alter the authors’ adherence to all the journal’s policies on sharing data and materials., (Copyright: © 2020 Kalbfleisch T et al.)

Background:  Genetic testing for pedigree accuracy is critical for managing genetic diversity in North American (NA) yak ( Bos grunniens ), a population expanded mostly from imported zoological park specimens.  DNA testing also enhances species conservation by identifying recent B. taurus F1 hybrid ancestors (within three generations).  Biallelic single nucleotide polymorphisms (SNPs) can accomplish either task, but increases the marker count and costs necessary to achieve both.  Our aim was to identify novel, multifunctional, triallelic yak SNPs (tySNPs), with each having two alleles for yak parentage testing, and a third allele for identifying recent cattle introgression.  Methods:   Genome sequences were aligned to the cattle UMD3.1 assembly and SNPs were screened for 1) heterozygosity in a NA and a Chinese yak, 2) a third allele at high frequency in cattle, and 3) flanking sequences conserved in both species.  Subsequently, tySNPs were filtered for unique alignment to the haplotype-resolved F1 yak assembly.  Allele frequencies were estimated in a subset of 87 tySNPs by genotyping 170 NA yak. Results:   We identified 610 autosomal tySNPs, distributed in 441 clusters with 5 Mb average genome spacing.  The average NA yak minor allele frequency was high (0.296), while average introgressed cattle alleles were low (0.004).  In simulations with tySNPs, 28 were sufficient for globally-unique animal identification (P I =5.81x10 -12 ), 87 were able to exclude 19 random bulls from parentage at the 99% level without using the dam's genotype (P E =5.3x10 -4 ), and 87 were able to detect F1 hybridization events after three generations of yak backcrosses (1/16th B. taurus germplasm). Conclusions :  Identifying animals, determining parentage and detecting recent hybridization events was efficient with as few as 87 tySNPs.  A similar triallelic approach could be used with other bottlenecked Bos species that hybridize with cattle, such as NA plains bison ( B. bison )., Competing Interests: Competing interests: The authors declare the following interest: co-authors RGT, JQ, and VB are full-time employees at Neogen Genomics, a company that provides agrigenomic and veterinary diagnostic services. There are no patents to declare. There is a genotyping product offered based on the methodology described in this publication. These interests to not alter the authors’ adherence to all the journal’s policies on sharing data and materials., (Copyright: © 2020 Kalbfleisch T et al.)

Background: Thrombomodulin-associated coagulopathy (TM-AC) is a rare bleeding disorder in which a single reported p.Cys537* variant in the thrombomodulin gene THBD causes high plasma thrombomodulin (TM) levels. High TM levels attenuate thrombin generation and delay fibrinolysis., Objectives: To report the characteristics of pedigree with a novel THBD variant causing TM-AC, and co-inherited deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI)., Patients/methods: Identification of pathogenic variants in hemostasis genes by next-generation sequencing and case recall for deep phenotyping., Results: Pedigree members with a previously reported THBD variant predicting p.Pro496Argfs*10 and chain truncation in TM transmembrane domain had abnormal bleeding and greatly increased plasma TM levels. Affected cases had attenuated thrombin generation and delayed fibrinolysis similar to previous reported TM&#95;AC cases with THBD p.Cys537*. Coincidentally, some pedigree members also harbored a stop-gain variant in CPB2 encoding TAFI. This reduced plasma TAFI levels but was asymptomatic. Pedigree members with TM-AC caused by the p.Pro496Argfs*10 THBD variant and also TAFI deficiency had a partially attenuated delay in fibrinolysis, but no change in the defective thrombin generation., Conclusions: These data extend the reported genetic repertoire of TM-AC and establish a common molecular pathogenesis arising from high plasma levels of TM extra-cellular domain. The data further confirm that the delay in fibrinolysis associated with TM-AC is directly linked to increased TAFI activation. The combination of the rare variants in the pedigree members provides a unique genetic model to develop understanding of the thrombin-TM system and its regulation of TAFI., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Milk production is one of the most important characteristics of dairy sheep, and the identification of genes affecting milk production traits is critical to understanding the genetics and improve milk production in future generations. Three statistical techniques, namely GWAS, ridge-regression BLUP and BayesC π , were used to identify SNPs in significant association with three milk production traits (milk yield, fat yield and protein yield) in a crossbred dairy sheep population. The results suggested that chromosomes 1, 3, 4, 5, 7 and 11 were likely to harbor genes important to milk production because these chromosomes had the greatest top-100-SNP variance contributions on the three milk production traits. The GWAS analysis identified between 74 and 288 genome-wide significant SNP (P < 0.05) whereas the BayesCπ model revealed between six and 63 SNPs, each with >95% posterior probability of inclusion as having a non-zero association effect on at least one of the three milk production traits. Positional candidate genes for milk production in sheep were searched, based on the sheep genomic assembly OAR version 3.1, such as those which map position coincided with or was located within 0.1 Mbp of a genome-wide suggestive or significant SNP. These identified SNPs and candidate genes supported some previous findings and also added new information about genetic markers for genetic improvement of lactation in dairy sheep, but keeping in mind that the majority of these positional candidate genes are not necessarily true causative loci for these traits and future validations are thus necessary., (© 2020 Stichting International Foundation for Animal Genetics.)

Three statistical models (an admixture model, linear regression, and ridge-regression BLUP) and two strategies for selecting SNP panels (uniformly spaced vs. maximum Euclidean distance of SNP allele frequencies between ancestral breeds) were compared for estimating genomic-estimated breed composition (GBC) in Brangus and Santa Gertrudis cattle, respectively. Animals were genotyped with a GeneSeek Genomic Profiler bovine low-density version 4 SNP chip. The estimated GBC was consistent among the uniformly spaced SNP panels, and values were similar between the three models. However, estimated GBC varied considerably between the three methods when using fewer than 10 000 SNPs that maximized the Euclidean distance of allele frequencies between the ancestral breeds. The admixture model performed most consistently across various SNP panel sizes. For the other two models, stabilized estimates were obtained with an SNP panel size of 20 000 SNPs or more. Based on the uniformly spaced 20K SNP panel, the estimated GBC was 69.8-70.5% Angus and 29.5-30.2% Brahman for Brangus, and 63.9-65.3% Shorthorn and 34.7-36.1% Brahman in Santa Gertrudis. The estimated GBC of ancestries for Santa Gertrudis roughly agreed with the pedigree-expected values. However, the estimated GBC in Brangus showed a considerably larger Angus composition than the pedigree-expected value (62.5%). The elevated Angus composition in the Brangus could be due to the mixture of some 1/2 Ultrablack animals (Brangus × Angus). Another reason could be the consequences of selection in Brangus cattle for phenotypes where the Angus breed has advantages., (© 2020 Stichting International Foundation for Animal Genetics.)

Clinical empathy is the ability to understand the patient's experience, communicate that understanding, and act on it. There is evidence that patient and physician benefits are associated with more empathic communications. These include higher patient and physician satisfaction, improved quality of life, and decreased professional burnout for physicians, as well as increased patient compliance with care plans. Empathy appears to decline during medical school, residency training, and early professional emergency medicine practice; however, brief training has the potential to improve behavioral measures of empathy. Improvements in emergency department physician empathy seems especially important in managing patients at elevated risk for opioid-related harm. We describe our conceptual approach to identifying and designing a practice improvement curriculum aimed to cultivate and improve behavioral empathy among practicing emergency physicians. Emergent themes from our preliminary study of interviews, focus groups, and workshops were identified and analyzed for feasibility, sensitivity to change, and potential impact. A conceptual intervention will address the following key categories: patient stigmatization, identification of problematic pain-subtypes, empathic communication skills, interactions with family and friends, and techniques to manage inappropriate patient requests. The primary outcomes will be the changes in behavioral empathy associated with training. An assessment battery was chosen to measure physician psychosocial beliefs, attitudes and behavior, communication skills, and burnout magnitude. Additional outcomes will include opioid prescribing practice, naloxone prescribing, and referrals to addiction treatment. A pilot study will allow an estimation of the intervention impact to help finalize a curriculum suitable for web-based national implementation., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)

Background: Whether the differences in brain structure and function, characteristic of adult major depressive disorder (MDD 1 ), are present in adolescent MDD is still unclear, but it has been shown that cognitive behavioral therapy (CBT 2 ) affects resting-state functional connectivity in both adult and adolescent MDD patients, with the claim that CBT has a normalizing effect on MDD-related functional disruption, but this has not been directly tested., Methods: 128 adolescent MDD patients and 40 adolescent controls were enrolled in the study. We investigated pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity. We also investigated the longitudinal effects of CBT on resting-state functional connectivity, and the relationship between pre-treatment functional disruption and CBT-related changes to resting-state functional connectivity was assessed by the correlation of pre-treatment cross-sectional effects and longitudinal CBT-related effects across multiple brain regions., Results: Patients had greater cortical thickness and white matter volume within fronto-limbic regions of the brain. Patients had greater pre-treatment resting-state functional connectivity within the default-mode, fronto-limbic, central-executive, and salience networks. CBT increased resting-state functional connectivity of the subgenual anterior cingulate and amygdala seeds with predominantly frontal regions. Regions showing the greatest pre-treatment functional disruption showed the weakest CBT-related changes., Limitations: For ethical reasons, there was no placebo group., Conclusions: Adolescent MDD is associated with structural and functional differences also seen in adult patients. CBT-related changes in resting-state functional connectivity do not appear to show a normalizing effect, but instead indicate rehabilitative effects on resting-state functional connectivity., Competing Interests: Declaration of Competing Interest Luca Villa, Professor Suckling, Dr. Wilkinson, Dr. Tait, and Professor Reynolds have no conflicts of interest to disclose. Professor Ian Goodyer has received consulting fees from Lundbeck Pharmaceuticals and is supported by a strategic award from the Wellcome Trust (095844/Z/11/Z). Dr. Raphael Kelvin has received consulting fees from Lundbeck Pharmaceuticals., (Copyright © 2020. Published by Elsevier B.V.)

Over the years, ad-hoc procedures were used for designing SNP arrays, but the procedures and strategies varied considerably case by case. Recently, a multiple-objective, local optimization (MOLO) algorithm was proposed to select SNPs for SNP arrays, which maximizes the adjusted SNP information (E score) under multiple constraints, e.g. on MAF, uniformness of SNP locations (U score), the inclusion of obligatory SNPs and the number and size of gaps. In the MOLO, each chromosome is split into equally spaced segments and local optima are selected as the SNPs having the highest adjusted E score within each segment, conditional on the presence of obligatory SNPs. The computation of the adjusted E score, however, is empirical, and it does not scale well between the uniformness of SNP locations and SNP informativeness. In addition, the MOLO objective function does not accommodate the selection of uniformly distributed SNPs. In the present study, we proposed a unified local function for optimally selecting SNPs, as an amendment to the MOLO algorithm. This new local function takes scalable weights between the uniformness and informativeness of SNPs, which allows the selection of SNPs under varied scenarios. The results showed that the weighting between the U and the E scores led to a higher imputation concordance rate than the U score or E score alone. The results from the evaluation of six commercial bovine SNP chips further confirmed this conclusion., (© 2020 Stichting International Foundation for Animal Genetics.)

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST-segment-elevation myocardial infarction. In the T-TIME (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low-dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T-TIME trial. From 2016 to 2017, patients with ST-segment-elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double-blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (<2, 2-4, and ≥4 hours) were prespecified. One hundred forty-four patients (mean age, 59±11 years; 80% male) were prospectively enrolled, representing 33% of the overall population (n=440). Overall, index of microcirculatory resistance (median, 29.5; interquartile range, 17.0-55.0), coronary flow reserve(1.4 [1.1-2.0]), and resistive reserve ratio (1.7 [1.3-2.3]) at the end of percutaneous coronary intervention did not differ between treatment groups. Interactions were observed between ischemic time and alteplase for coronary flow reserve ( P =0.013), resistive reserve ratio ( P =0.026), and microvascular obstruction ( P =0.022), but not index of microcirculatory resistance. Conclusions In ST-segment-elevation myocardial infarction with ischemic time ≤6 hours, there was overall no difference in microvascular function with alteplase versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02257294.

Ageing people with hemophilia (PWH) have a higher prevalence of hypertension than the general population. This study aimed to determine whether macroscopic hematuria was associated with hypertension in PWH in a post hoc analysis using data from a cross-sectional study conducted by the ADVANCE Working Group (the H3 study), which included PWH ≥ 40 years of age. Data from 16 contributing centers, located in 13 European countries and Israel, were analyzed using logistic regression models. Of 532 recruited PWH in the H3 study, 117 had hypertension and a positive family history of hypertension (hypertension FH+), 75 had hypertension and a negative family history of hypertension (hypertension FH-), 290 had no diagnosis of hypertension, and the remaining 50 had missing hypertension data. Logistic regressions showed that macroscopic hematuria was associated with hypertension FH+, both in the univariate (OR = 1.84 [1.17-2.90], P = .01) and in the multivariate model (OR = 1.80 [1.03-3.16], P = .04). Macroscopic hematuria was not associated with hypertension FH-. Moreover, in a multivariate logistic regression the odds of hypertension FH+ were increased with the number of macroscopic hematuria episodes. The association between macroscopic hematuria and hypertension was significant for PWH with a family history of hypertension.

Introduction: Macroscopic hematuria is considered a significant risk factor for urologic disease, and it is highly prevalent in people with hemophilia., Aim: To determine whether prophylactic factor replacement therapy is associated with reduced occurrence of macroscopic hematuria in people with hemophilia in a post hoc analysis using data from a cross-sectional study conducted by the Age-Related Developments and Comobordities in Hemophilia (ADVANCE) Working Group that included males with hemophilia ≥40 years of age., Methods: Data from 16 contributing centers, in 13 European countries and Israel, were analyzed using logistic regression. Of 532 recruited individuals, this analysis included 370 patients with moderate or severe hemophilia who received on-demand or prophylactic therapy., Results: For patients with a history of macroscopic hematuria, we analyzed the association between prophylaxis and reoccurrence of macroscopic hematuria within the past 5 years (n = 235 patients). Frequent (≥3 times/wk) prophylaxis was negatively associated with a recent episode of macroscopic hematuria (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.76). We also analyzed whether prophylaxis corresponded to a lower lifetime number of macroscopic hematuria episodes (n = 285 patients). Frequent prophylaxis for >15 years was associated with a lower number of episodes compared to on-demand treatment (OR, 0.29; 95% CI, 0.16-0.54), whereas nonsteroidal anti-inflammatory drugs (NSAIDs) and severe hemophilia were associated with a higher number. There was no association of prophylaxis <3 times/wk with hematuria., Conclusion: Frequent prophylaxis was negatively associated with the number of episodes of macroscopic hematuria in people with hemophilia. Prevalence of macroscopic hematuria was higher among individuals with severe hemophilia and those regularly using NSAIDs., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

SNP arrays are widely used in genetic research and agricultural genomics applications, and the quality of SNP genotyping data is of paramount importance. In the present study, SNP genotyping concordance and discordance were evaluated for commercial bovine SNP arrays based on two types of quality assurance (QA) samples provided by Neogen GeneSeek. The genotyping discordance rates (GDRs) between chips were on average between 0.06% and 0.37% based on the QA type I data and between 0.05% and 0.15% based on the QA type II data. The average genotyping error rate (GER) pertaining to single SNP chips, based on the QA type II data, varied between 0.02% and 0.08% per SNP and between 0.01% and 0.06% per sample. These results indicate that genotyping concordance rate was high (i.e. from 99.63% to 99.99%). Nevertheless, mitochondrial and Y chromosome SNPs had considerably elevated GDRs and GERs compared to the SNPs on the 29 autosomes and X chromosome. The majority of genotyping errors resulted from single allotyping errors, which also included the opposite instances for allele 'dropout' (i.e. from AB to AA or BB). Simultaneous allotyping errors on both alleles (e.g. mistaking AA for BB or vice versa) were relatively rare. Finally, a list of SNPs with a GER greater than 1% is provided. Interpretation of association effects of these SNPs, for example in genome-wide association studies, needs to be taken with caution. The genotyping concordance information needs to be considered in the optimal design of future bovine SNP arrays., (© 2019 Stichting International Foundation for Animal Genetics.)

Single nucleotide polymorphism (SNP) chips have been widely used in genetic studies and breeding applications in animal and plant species. The quality of SNP genotypes is of paramount importance. More often than not, there are situations in which a number of genotypes may fail, requiring them to be imputed. There are also situations in which ungenotyped loci need to be imputed between different chips, or high-density genotypes need to be imputed based on low-density genotypes. Under these circumstances, the validity and reliability of subsequent data analyses is subject to the accuracy of these imputed genotypes. For justifying a better understanding of factors affecting imputation accuracy, in the present study, the impacts of SNP genotyping call rate and SNP genotyping error rate on the accuracy of genotype imputation were investigated under two scenarios in 20 116 U.S. Holstein cattle, each genotyped with a GGP 50K SNP chip. When the two factors were not correlated in scenario 1, simulated genotyping call rate varied from 50% to 100% and simulated genotyping error rate changed from 0% to 50%, with both factors being independent of each other. In scenario 2, genotyping error rates were correlated with genotyping call rate, and the relationship was set up by fitting a linear regression model between the two variables on a real dataset. That is, the simulated SNP call rate varied from 100% to 50% whereas the SNP genotyping rate changed from 0% to 13.55%. Finally, a 5-fold cross-validation was used to assess the subsequent imputation accuracy. The results showed that when original SNP genotyping call rate were independent of SNP genotyping error rate, the imputation accuracy did not change significantly with the original genotyping call rate (P>0.05), but it decreased significantly as the genotyping error rate increased (P<0.01). However, when original genotyping call rate was negatively correlated with genotyping error rate, the imputation error increased with elevated original genotyping error rate. In both scenarios, genotyping call rate needs to be no less than 0.90 in order to obtain 98% or higher genotype imputation accuracy. The present results can provide guidance for establishing quality assurance criteria for SNP genotyping in practice.

Genetic variation in the serotonin transporter gene ( SLC6A4 ) is associated with vulnerability to affective disorders and pharmacotherapy efficacy. We recently identified sequence polymorphisms in the common marmoset SLC6A4 repeat region (AC/C/G and CT/T/C) associated with individual differences in anxiety-like trait, gene expression, and response to antidepressants. The mechanisms underlying the effects of these polymorphisms are unknown, but a key mediator of serotonin action is the serotonin 2A receptor (5HT 2A ). Thus, we correlated 5HT 2A binding potential (BP) and RNA gene expression in 16 SLC6A4 genotyped marmosets with responsivity to 5HT 2A antagonism during the human intruder test of anxiety. Voxel-based analysis and RNA measurements showed a reduction in 5HT 2A BP and gene expression specifically in the right posterior insula of individuals homozygous for the anxiety-related variant AC/C/G. These same marmosets displayed an anxiogenic, dose-dependent response to the human intruder after 5HT 2A pharmacological antagonism, while CT/T/C individuals showed no effect. A voxel-based correlation analysis, independent of SLC6A4 genotype, revealed that 5HT 2A BP in the adjacent right anterior insula and insula proisocortex was negatively correlated with trait anxiety scores. Moreover, 5HT 2A BP in both regions was a good predictor of the size and direction of the acute emotional response to the human intruder threat after 5HT 2A antagonism. Our findings suggest that genetic variation in the SLC6A4 repeat region may contribute to the trait anxious phenotype via neurochemical changes in brain areas implicated in interoceptive and emotional processing, with a critical role for the right insula 5HT 2A in the regulation of affective responses to threat., Competing Interests: The authors declare no conflict of interest.

While the association between heavy alcohol consumption and aggression has been well documented, the causal direction of this association, particularly at a population level, is disputed. A number of causal sequences have been proposed. First, that aggression leads to heavy alcohol use. Second, that heavy alcohol use leads to aggression. Third, that the association between alcohol use and aggression is due to confounding by (a) sociodemographic variables or (b) delinquency. We report here data from four Australasian prospective longitudinal studies of adolescents, to assess the temporal sequence of heavy drinking and aggression over the period from adolescence to young adulthood. The four cohort studies provide a total sample of 6,706 persons (Australian Temperament Project, n = 1701; Christchurch Health and Development Study, n = 931; Mater-University of Queensland Study of Pregnancy, n = 2437; Victorian Adolescent Health Cohort Study, n = 1637). We use multinomial logistic regression to determine whether early adolescent aggression predicts subsequent age of onset of heavy episodic drinking (HED), after adjustment for concurrent sociodemographic factors and delinquency. We then consider whether HED predicts subsequent aggression, after adjusting for past aggression, concurrent delinquency, and a range of confounders. There are broadly consistent findings across the four cohort studies. Early aggression strongly predicts subsequent HED. HED predicts later aggression after adjustment for prior aggression and other confounders. Policies that alter population levels of alcohol consumption are likely to impact on levels of aggression in societies where HED linked to aggression is more common., (© 2019 Wiley Periodicals, Inc.)

Long-range surface plasmon polariton waveguides consisting of Au stripes integrated with input and output grating couplers embedded in thick Cytop claddings are proposed and demonstrated experimentally. Under the right conditions, grating couplers enable broadside (top) coupling with good efficiency while producing a low level of background light. The scheme does not require high-quality input and output edge facets, and it simplifies optical alignments. We demonstrate coupling using a cleaved bow-tie fiber and a lensed fiber, and we determine the grating coupling efficiencies in both cases over a broad operating wavelength range. The lensed fiber produces a better overlap with the long-range surface plasmon mode of interest and thus results in a better coupling efficiency with essentially no background light as observed on an infrared camera. The measurements are compared with theoretical results obtained using a realistic model of the structures, including out-of-plane curvature in the grating profile resulting from our fabrication process. The coupling scheme along with the surface plasmon waveguides hold strong potential for biosensing applications.

In last few decades, micro- and nano-fabrication techniques based on photolithography and electron beam lithography have advanced greatly, mainly in the field of semiconductor fabrication. Such techniques are generally transferrable to the fabrication of plasmonic structures and metamaterials. However, plasmonic devices often require a transparent insulating substrate to be operational at visible or near-infrared wavelengths. Here we report a resist-on-metal bilayer lift-off technique enabling the fabrication of plasmonic structures on insulating substrates. The metal layer under the resist eliminates major difficulties in lithography, such as charging during electron beam exposure and uncontrolled diffuse optical scattering during photolithography. In addition, the resist-on-metal bilayer can be migrated to different substrates with minimal process alteration, because the material properties of the substrate, such as secondary electron emission or optical reflectance, become irrelevant due to the shielding provided by the metal layer. As demonstrations, we fabricate large-scale plasmonic waveguides and Bragg gratings, adiabatically-modulated plasmonic waveguide couplers, and plasmonic nanoantenna arrays using the resist-on-metal bilayer lift-off process. The process can also be used to define structures formed of other materials such as dielectrics.

Background: Bovine respiratory disease complex (BRDC) is one of the most important sources of loss within the beef cattle industry in the USA. Steps have been taken to reduce the incidence of BRDC through vaccination. Despite the effectiveness of vaccines, large proportions of cattle still experience morbidity and mortality. Identification of genomic regions that are associated with variation in response to vaccination would allow for the selection of individuals genetically predisposed to respond to vaccination based on specific markers, while heritability and accuracy estimates would help facilitate genomic selection. This in turn may lead to selection for beef cattle herds that may have lower incidence rate of BRDC after vaccination. This study utilizes an Angus herd of more than 2000 head of cattle to identify these regions of association., Results: Genome wide association studies were performed for viral neutralization antibody level and response to vaccination traits against four different viruses associated with BRDC: bovine viral diarrhea virus 1 and 2 (BVDV1 and BVDV2), bovine respiratory syncytial virus (BRSV), and bovine herpesvirus (BHV1). A total of six 1-Mb windows were associated with greater than 1% of the genetic variance for the analyzed vaccination response traits. Heritabilities ranged from 0.08 to 0.21 and prediction accuracy ranged from 0.01 to 0.33 across 7 different vaccination traits., Conclusions: Although six 1-Mb windows were identified as associated with 1% or greater genetic variance for viral neutralization antibody level and response to vaccination traits, few genes around these windows could readily be considered candidates. This indicates the need for further functional genomic annotation, as these regions appear to be gene deserts. Traits ranged from lowly to moderately heritable, which indicated the potential for selection of individuals that are genetically pre-disposed to respond to vaccination. The relatively low amount of genetic variance accounted for by any 1-Mb window indicated that viral neutralization antibody level and response to vaccination traits are polygenic in nature. Selection for these traits is possible, but likely to be slow due to the low heritabilities and absence of markers with high genetic variation associated with them.

Importance: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction (STEMI) and is associated with adverse outcomes., Objective: To determine whether a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion will reduce microvascular obstruction., Design, Setting, and Participants: Between March 17, 2016, and December 21, 2017, 440 patients presenting at 11 hospitals in the United Kingdom within 6 hours of STEMI due to a proximal-mid-vessel occlusion of a major coronary artery were randomized in a 1:1:1 dose-ranging trial design. Patient follow-up to 3 months was completed on April 12, 2018., Interventions: Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145) by manual infusion over 5 to 10 minutes. The intervention was scheduled to occur early during the primary PCI procedure, after reperfusion of the infarct-related coronary artery and before stent implant., Main Outcomes and Measures: The primary outcome was the amount of microvascular obstruction (% left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging (MRI) conducted from days 2 through 7 after enrollment. The primary comparison was the alteplase 20-mg group vs the placebo group; if not significant, the alteplase 10-mg group vs the placebo group was considered a secondary analysis., Results: Recruitment stopped on December 21, 2017, because conditional power for the primary outcome based on a prespecified analysis of the first 267 randomized participants was less than 30% in both treatment groups (futility criterion). Among the 440 patients randomized (mean age, 60.5 years; 15% women), the primary end point was achieved in 396 patients (90%), 17 (3.9%) withdrew, and all others were followed up to 3 months. In the primary analysis, the mean microvascular obstruction did not differ between the 20-mg alteplase and placebo groups (3.5% vs 2.3%; estimated difference, 1.16%; 95% CI, -0.08% to 2.41%; P = .32) nor in the analysis of 10-mg alteplase vs placebo groups (2.6% vs 2.3%; estimated difference, 0.29%; 95% CI, -0.76% to 1.35%; P = .74). Major adverse cardiac events (cardiac death, nonfatal MI, unplanned hospitalization for heart failure) occurred in 15 patients (10.1%) in the placebo group, 18 (12.9%) in the 10-mg alteplase group, and 12 (8.2%) in the 20-mg alteplase group., Conclusions and Relevance: Among patients with acute STEMI presenting within 6 hours of symptoms, adjunctive low-dose intracoronary alteplase given during the primary percutaneous intervention did not reduce microvascular obstruction. The study findings do not support this treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT02257294.

Natural and artificial selection, geographical segregation and genetic drift can result in differentiation of allelic frequencies of single nucleotide polymorphism (SNP) at many loci in the animal genome. For individuals whose ancestors originated from different populations, their genetic compositions exhibit multiple components correlated with the genotypes or allele frequencies of these breeds or populations. Therefore, by using an appropriate statistical method, one can estimate the genomic contribution of each breed (ancestor) to the genome of each individual animal, which is referred to as the genomic breed composition (GBC). This paper reviews the principles, statistical methods and steps for estimating GBC of individual animals using SNP genotype data. Based on a linear regression model and an admixture model respectively, the protocols were demonstrated by the breed characterization of 198 purported Akaushi cattle, which included selection of reference SNPs and reference individual animals, and computing GBC for animals to be evaluated. The reference populations consist of 36 574 cattle from five cattle breeds (Akaushi, Angus, Hereford, Holstein and Jersey), each genotyped on either a 40K or 50K SNP chip. Four common SNP panels scanned from commercial chips for estimating GBC of individual animals are optimally selected, thereby expanding the functionalities of the currently available commercial SNP chips. It remains to be explored in future studies as to how estimated GBC can be incorporated to improve the accuracies on genomic prediction in purebred animals and crossbreds as well.

Violations of rules and regulations in research can cause significant problems for human participants, animal subjects, data integrity, institutions, and investigators. The Professionalism and Integrity in Research Program (PI Program) provides remediation training that addresses the root causes of violations of rules and regulations in research. Through assessments, a three-day workshop, and follow-up coaching calls, the PI Program teaches evidence-based decision-making strategies designed to help researchers to compensate for bias, uncertainty, and work-related stress, and foster the skills needed to oversee research projects in today's complex regulatory environments. Across its first three years (2013-2015), the program trained 39 researchers from 24 different institutions in the United States. Participant evaluations of the program's faculty and workshop content were highly positive (4.7-4.8 and 4.5-4.6, respectively, on a 5-point scale). Preliminary program outcome assessment using validated measures of professional decision making and cognitive distortions in a pre- and postworkshop design indicated significant improvements. A follow-up survey of participants found statistically significant increases in a variety of target behaviors, including training research staff members to foster compliance and research quality, using standard operating procedures to support compliance and research integrity, performing self-audits of research operations, reducing job stressors, actively overseeing the work of the research team, and seeking help when experiencing uncertainty. Assessment of the PI Program was conducted with modest sample sizes, yet evaluation, outcome assessment, and self-reported survey data provided statistically significant evidence of effectiveness in achieving program goals.

Single-mode surface plasmon distributed feedback (DFB) lasers are realized in the near infrared using a two-dimensional non-uniform long-range surface plasmon polariton structure. The surface plasmon mode is excited onto a 20 nm-thick, 1 μm-wide metal stripe (Ag or Au) on a silica substrate, where the stripe is stepped in width periodically, forming a 1st order Bragg grating. Optical gain is provided by optically pumping a 450 nm-thick IR-140 doped PMMA layer as the top cladding, which covers the entire length of the Bragg grating, thus creating a DFB laser. Single-mode lasing peaks of very narrow linewidth were observed for Ag and Au DFBs near 882 nm at room temperature. The narrow linewidths are explained by the low spontaneous emission rate into the surface plasmon lasing mode as well as the high quality factor of the DFB structure. The lasing emission is exclusively TM polarized. Kinks in light-light curves accompanied by spectrum narrowing were observed, from which threshold pump power densities can be clearly identified (0.78 MW cm-2 and 1.04 MW cm-2 for Ag and Au DFB lasers, respectively). The Schawlow-Townes linewidth for our Ag and Au DFB lasers is estimated and very narrow linewidths are predicted for the lasers. The lasers are suitable as inexpensive, recyclable and highly coherent sources of surface plasmons, or for integration with other surface plasmon elements of similar structure.

Reliable genomic prediction of breeding values for quantitative traits requires the availability of sufficient number of animals with genotypes and phenotypes in the training set. As of 31 October 2016, there were 3,797 Brangus animals with genotypes and phenotypes. These Brangus animals were genotyped using different commercial SNP chips. Of them, the largest group consisted of 1,535 animals genotyped by the GGP-LDV4 SNP chip. The remaining 2,262 genotypes were imputed to the SNP content of the GGP-LDV4 chip, so that the number of animals available for training the genomic prediction models was more than doubled. The present study showed that the pooling of animals with both original or imputed 40K SNP genotypes substantially increased genomic prediction accuracies on the ten traits. By supplementing imputed genotypes, the relative gains in genomic prediction accuracies on estimated breeding values (EBV) were from 12.60% to 31.27%, and the relative gain in genomic prediction accuracies on de-regressed EBV was slightly small (i.e. 0.87%-18.75%). The present study also compared the performance of five genomic prediction models and two cross-validation methods. The five genomic models predicted EBV and de-regressed EBV of the ten traits similarly well. Of the two cross-validation methods, leave-one-out cross-validation maximized the number of animals at the stage of training for genomic prediction. Genomic prediction accuracy (GPA) on the ten quantitative traits was validated in 1,106 newly genotyped Brangus animals based on the SNP effects estimated in the previous set of 3,797 Brangus animals, and they were slightly lower than GPA in the original data. The present study was the first to leverage currently available genotype and phenotype resources in order to harness genomic prediction in Brangus beef cattle., (© 2018 Blackwell Verlag GmbH.)

Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology., (© 2017 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a characteristic overeating disorder, mild to moderate intellectual disability, and a variable range of social and behavioral difficulties. Consequently, widespread alterations in neural structure and developmental and maturational trajectory would be expected. To date, there have been few quantitative and systematic studies of brain morphology in PWS, although alterations of volume and of cortical organisation have been reported. This study aimed to investigate, in detail, the structure of grey matter and cortex in the brain in a sample of young adults with PWS in a well-matched case-controlled analysis. 20 young adults with PWS, aged 19-27 years, underwent multiparameter mapping magnetic resonance imaging sequences, from which measures of grey matter volume, cortical thickness and magnetisation transfer saturation, as a proxy measure of myelination, were examined. These variables were investigated in comparison to a control group of 40 typically developing young adults, matched for age and sex. A voxel-based morphometry analysis identified large and widespread bilateral clusters of both increased and decreased grey matter volume in the brain in PWS. In particular, widespread areas of increased volume encompassed parts of the prefrontal cortex, especially medially, the majority of the cingulate cortices, from anterior to posterior aspects, insula cortices, and areas of the parietal and temporal cortices. Increased volume was also reported in the caudate, putamen and thalamus. The most ventromedial prefrontal areas, in contrast, showed reduced volume, as did the parts of the medial temporal lobe, bilateral temporal poles, and a small cluster in the right lateral prefrontal cortex. Analysis of cortical structure revealed that areas of increased volume in the PWS group were largely driven by greater cortical thickness. Conversely, analysis of myelin content using magnetisation transfer saturation indicated that myelination of the cortex was broadly similar in the PWS and control groups, with the exception of highly localised areas, including the insula. The bilateral nature of these abnormalities suggests a systemic biological cause, with possible developmental and maturational mechanisms discussed, and may offer insight into the contribution of imprinted genes to neural development.

Background: Warfarin acts by inhibiting the reduction of vitamin K (VK) to its active form, thereby decreasing the production of VK-dependent coagulation proteins. The aim of this research is to develop a joint model for the VK-dependent clotting factors II, VII, IX and X, and the anticoagulation proteins, proteins C and S, during warfarin initiation., Methods: Data from 18 patients with atrial fibrillation who had warfarin therapy initiated were available for analysis. Nine blood samples were collected from each subject at baseline, and at 1-5, 8, 15 and 29 days after warfarin initiation and assayed for factors II, VII, IX and X, and proteins C and S. Warfarin concentration-time data were not available. The coagulation proteins data were modelled in a stepwise manner using NONMEM ® Version 7.2. In the first stage, each of the coagulation proteins was modelled independently using a kinetic-pharmacodynamic model. In the subsequent step, the six kinetic-pharmacodynamic models were combined into a single joint model., Results: One patient was administered VK and was excluded from the analysis. Each kinetic-pharmacodynamic model consisted of two parts: (1) a common one-compartment pharmacokinetic model with first-order absorption and elimination for warfarin; and (2) an inhibitory E max model linked to a turnover model for coagulation proteins. In the joint model, an unexpected pharmacodynamic lag was identified and the estimated degradation half-life of VK-dependent coagulation proteins were in agreement with previously published values. The model provided an adequate fit to the observed data., Conclusion: The joint model represents the first work to quantify the influence of warfarin on all six VK-dependent coagulation proteins simultaneously. Future work will expand the model to predict the influence of exogenously administered VK on the time course of clotting factor concentrations after warfarin overdose and during perioperative warfarin reversal procedures.

Although vaccination is an effective measure in reducing the risk of bovine respiratory disease complex (BRDC) in cattle, BRDC losses remain significant. Increasing the efficacy of vaccination depends on elucidating the protective immune response to different antigens included in vaccines, determining the best timing for vaccination, and understanding the impact of the age of the calf on vaccination. This study measured the serum antibodies present in calves following vaccination against 4 viruses commonly associated with BRDC: bovine viral diarrhea virus type 1 and 2 (BVDV1 and BVDV2), bovine respiratory syncytial virus (BRSV), and bovine herpesvirus 1 (BHV1). Serum antibody titers were measured in more than 1,600 calves at 3-wk intervals starting at the time of the first vaccination. This first vaccination occurred at weaning for approximately half of the individuals and 3 wk before weaning for the other half. Dam age (years), time of weaning (initial vaccination or booster vaccination), and age of calf within year-season (days within year-season) classification all were found to have a significant effect on measured traits such as the initial titer and overall response. An increased initial titer was negatively correlated with each response trait (initial, booster, and overall response). Calves that were weaned at initial vaccination had greater overall antibody response to BVDV1 and BVDV2 compared with calves weaned 3 wk before initial vaccination. In contrast, calves given their initial vaccination 3 wk before weaning had greater overall antibody response to BRSV and BHV1 compared with calves that were vaccinated at weaning. Furthermore, the circulating antibody titer at which each virus needed to be below for an individual calf to positively respond to vaccination was determined (log titer of 0.38 for BVDV1, 1.5 for BVDV2, 3.88 for BRSV, and 1.5 for BHV1). This information can be used to improve vaccination protocols to allow for a greater response rate of individuals to vaccination and, hopefully, improved protection.

There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and 'missed' rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence., (© 2016 Society for the Study of Addiction.)

We previously have shown that plasma concentrations of endocannabinoids (EC) are positively correlated with feed efficiency and leaner carcasses in finishing steers. However, whether the animal growth during the finishing period affects the concentration of EC is unknown. The objective of this study was to quantify anandamide (AEA) and 2-arachidonyl glycerol (2-AG) in plasma during different stages of the finishing period and identify possible associations with production traits and carcass composition in beef calves. Individual DMI and BW gain were measured on 236 calves ( = 127 steers and = 109 heifers) for 84 d on a finishing ration. Blood samples were collected on d 0 (early), 42 (mid), and 83 (late) of days on study (DOS). Cattle were slaughtered 44 d after the feeding study. Plasma concentration of AEA at 0 DOS was indirectly associated with the G:F ( < 0.01) and directly associated with residual feed intake (RFI; < 0.05) in steers. In contrast, plasma concentration of AEA at 83 DOS was directly associated with the G:F and indirectly associated RFI in heifers and steers ( < 0.01). In addition, AEA concentration at 42 and 83 DOS was positively associated with ADG and DMI ( < 0.01) in heifers and steers. Furthermore, 2-AG concentration at 42 DOS was positively associated with ADG in steers ( < 0.01) and heifers ( < 0.10). Plasma concentration of AEA was positively associated ( < 0.05) with HCW, USDA-calculated yield grade, and 12th-rib fat thickness in heifers, whereas no associations were found in steers. In contrast, 2-AG concentration was not associated with any carcass traits. These results provide evidence that circulating EC change during animal growth and that AEA concentration may be a useful predictor of growth and feed efficiency and, in females, of carcass attributes.

Compared to female major depressive disorder (MDD), male MDD often receives less attention. However, research is warranted since there are significant sex differences in the clinical presentation of MDD and a higher rate of suicide in depressed men. To the best of our knowledge, this is the first functional magnetic resonance imaging (fMRI) study with a large sample addressing putative sex differences in MDD during adolescence, a period when one of the most robust findings in psychiatric epidemiology emerges; that females are twice as likely to suffer from MDD than males. Twenty-four depressed and 10 healthy male adolescents, together with 82 depressed and 24 healthy female adolescents, aged 11-18 years, undertook an affective go/no-go task during fMRI acquisition. In response to sad relative to neutral distractors, significant sex differences (in the supramarginal gyrus) and group-by-sex interactions (in the supramarginal gyrus and the posterior cingulate cortex) were found. Furthermore, in contrast to the healthy male adolescents, depressed male adolescents showed decreased activation in the cerebellum with a significant group-by-age interaction in connectivity. Future research may consider altered developmental trajectories and the possible implications of sex-specific treatment and prevention strategies for MDD.

Acquired haemophilia is a rare disease in which bleeding is more severe than in hereditary haemophilia and usually occurs in the soft tissues, the gastrointestinal tract, or the mucous membranes. There have been only a few presentations of spontaneous sublingual haematoma in acquired haemophilia, but prompt management of the airway and identification of the underlying cause was crucial in all., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background/aim: The safety of amateur and professional boxing is a contentious issue. We hypothesised that advanced magnetic resonance imaging and neuropsychological testing could provide evidence of acute and early brain injury in amateur boxers., Methods: We recruited 30 participants from a university amateur boxing club in a prospective cohort study. Magnetic resonance imaging (MRI) and neuropsychological testing was performed at three time points: prior to starting training; within 48 h following a first major competition to detect acute brain injury; and one year follow-up. A single MRI acquisition was made from control participants. Imaging analysis included cortical thickness measurements with Advanced Normalization Tools (ANTS) and FreeSurfer, voxel based morphometry (VBM), and Tract Based Spatial Statistics (TBSS). A computerized battery of neuropsychological tests was performed assessing attention, learning, memory and impulsivity., Results: During the study period, one boxer developed seizures controlled with medication while another developed a chronic subdural hematoma requiring neurosurgical drainage. A total of 10 boxers contributed data at to the longitudinal assessment protocol. Reasons for withdrawal were: logistics (10), stopping boxing (7), withdrawal of consent (2), and development of a chronic subdural hematoma (1). No significant changes were detected using VBM, TBSS, cortical thickness measured with FreeSurfer or ANTS, either cross-sectionally at baseline, or longitudinally. Neuropsychological assessment of boxers found attention/concentration improved over time while planning and problem solving ability latency decreased after a bout but recovered after one year., Conclusion: While this neuroimaging and neuropsychological assessment protocol could not detect any evidence of brain injury, one boxer developed seizures and another developed a chronic sub-dural haematoma.

Naltrexone is an opioid receptor antagonist used in the management of alcohol dependence. Although the endogenous opioid system has been implicated in emotion regulation, the effects of mu-opioid receptor blockade on brain systems underlying negative emotional processing are not clear in addiction. Individuals meeting criteria for alcohol dependence alone (n=18, alcohol) and in combination with cocaine and/or opioid dependence (n=21, alcohol/drugs) and healthy individuals without a history of alcohol or drug dependence (n=21) were recruited. Participants were alcohol and drug abstinent before entered into this double-blind, placebo-controlled, randomized, crossover study. Functional magnetic resonance imaging was used to investigate brain response while viewing aversive and neutral images relative to baseline on 50 mg of naltrexone and placebo. We found that naltrexone modulated task-related activation in the medial prefrontal cortex and functional connectivity between the anterior cingulate cortex and the hippocampus as a function of childhood adversity (for aversive versus neutral images) in all groups. Furthermore, there was a group-by-treatment-by-condition interaction in the right amygdala, which was mainly driven by a normalization of response for aversive relative to neutral images under naltrexone in the alcohol/drugs group. We conclude that early childhood adversity is one environmental factor that influences pharmacological response to naltrexone. Pharmacotherapy with naltrexone may also have some ameliorative effects on negative emotional processing in combined alcohol and drug dependence, possibly due to alterations in endogenous opioid transmission or the kappa-opioid receptor antagonist actions of naltrexone.

Imaging studies have implicated altered functional connectivity in adults with major depressive disorder (MDD). Whether similar dysfunction is present in adolescent patients is unclear. The degree of resting-state functional connectivity (rsFC) may reflect abnormalities within emotional ('hot') and cognitive control ('cold') neural systems. Here, we investigate rsFC of these systems in adolescent patients and changes following cognitive behavioral therapy (CBT). Functional Magnetic Resonance Imaging (fMRI) was acquired from adolescent patients before CBT, and 24-weeks later following completed therapy. Similar data were obtained from control participants. Cross-sectional Cohort: From 82 patients and 34 controls at baseline, rsFC of the amygdala, anterior cingulate cortex (ACC), and pre-frontal cortex (PFC) was calculated for comparison. Longitudinal Cohort: From 17 patients and 30 controls with longitudinal data, treatment effects were tested on rsFC. Patients demonstrated significantly greater rsFC to left amygdala, bilateral supragenual ACC, but not with PFC. Treatment effects were observed in right insula connected to left supragenual ACC, with baseline case-control differences reduced. rsFC changes were significantly correlated with changes in depression severity. Depressed adolescents exhibited heightened connectivity in regions of 'hot' emotional processing, known to be associated with depression, where treatment exposure exerted positive effects, without concomitant differences in areas of 'cold' cognition., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)