High genetic merit dairy heifers grazing low quality forage had similar weight gain and urinary nitrogen excretion to those of low genetic merit heifers.

Climate variability and increasing drought events have become significant concerns in recent years. However, there is limited published research on body weight (BW) change of dairy heifers with different genetic merit when grazing on drought impacted pastures in southern Australia. Achieving target body weight (BW) is vital for dairy heifers, especially during critical stages like mating and calving. This study aimed to assess dry matter (DM) intake, BW change, urinary nitrogen excretion, and grazing behaviours of high vs. low genetic dairy heifers grazing pasture during a 43-day experimental period in a drought season. Forty-eight Holstein Friesian heifers grazed on ryegrass-dominant pasture and were divided into two groups based on their high and low Balanced Performance Index (HBPI and LBPI, respectively). Each group was further stratified into six plots, with similar BW, resulting in four heifers per replication group. Data from the five measurement days were averaged for individual cows to analyse the dry matter intake, nitrogen intake and nitrogen excretion. The statistical model included the treatment effect of BPI (H and L) and means were analysed using ANOVA. The pasture quality was poor, with metabolizable energy 9.3 MJ/Kg DM and crude protein 5.9% on a DM basis. Nitrogen intake and urinary nitrogen excretion were significantly higher (p < 0.05) in HBPI compared to the LBPI. However, despite these differences, the study did not find any advantages of having HBPI heifer grazing on low quality forage in terms of BW performance.

NF-κB Signaling-Mediated Activation of WNK-SPAK-NKCC1 Cascade in Worsened Stroke Outcomes of Ang II-Hypertensive Mice.

BACKGROUND: Worsened stroke outcomes with hypertension comorbidity are insensitive to blood pressure-lowering therapies. In an experimental stroke model with comorbid hypertension, we investigated causal roles of ang II (angiotensin II)-mediated stimulation of the brain WNK (with no lysine [K] kinases)-SPAK (STE20/SPS1-related proline/alanine-rich kinase)-NKCC1 (Na-K-Cl cotransporter) complex in worsened outcomes. METHODS: Saline- or ang II-infused C57BL/6J male mice underwent stroke induced by permanent occlusion of the distal branches of the middle cerebral artery. Mice were randomly assigned to receive either vehicle dimethyl sulfoxide/PBS (2 mL/kg body weight/day, IP), a novel SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (ZT-1a' 5 mg/kg per day, IP) or a NF-κB (nuclear factor-κB) inhibitor TAT-NBD (transactivator of transcription-NEMO-binding domain' 20 mg/kg per day, IP). Activation of brain NF-κB and WNK-SPAK-NKCC1 cascade as well as ischemic stroke outcomes were examined. RESULTS: Stroke triggered a 2- to 5-fold increase of WNK (isoforms 1, 2, 4), SPAK/OSR1 (oxidative stress-responsive kinase 1), and NKCC1 protein in the ang II-infused hypertensive mouse brains at 24 hours after stroke, which was associated with increased nuclear translocation of phospho-NF-κB protein in the cortical neurons (a Pearson correlation r of 0.77, P<0.005). The upregulation of WNK-SPAK-NKCC1 cascade proteins resulted from increased NF-κB recruitment on Wnk1, Wnk2, Wnk4, Spak, and Nkcc1 gene promoters and was attenuated by NF-κB inhibitor TAT-NBD. Poststroke administration of SPAK inhibitor ZT-1a significantly reduced WNK-SPAK-NKCC1 complex activation, brain lesion size, and neurological function deficits in the ang II-hypertensive mice without affecting blood pressure and cerebral blood flow. CONCLUSIONS: The ang II-induced stimulation of NF-κB transcriptional activity upregulates brain WNK-SPAK-NKCC1 cascade and contributes to worsened ischemic stroke outcomes, illustrating the brain WNK-SPAK-NKCC1 complex as a therapeutic target for stroke with comorbid hypertension.

Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice.

New research shows that disease-associated microglia in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pH (pHi) is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H+ in exchange of Na+ influx. We report here that post-stroke Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The other upregulated genes included genes for phagocytosis and LXR/RXR pathway activation as well as the disease-associated microglia hallmark genes (Apoe, Trem2, Spp1). The cKO microglia exhibited increased oxidative phosphorylation capacity, and higher phagocytic activity, which likely played a role in enhanced synaptic stripping and remodeling, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated oxidative phosphorylation immunometabolism, and boosted phagocytosis function which is associated with tissue remodeling and post-stroke cognitive function recovery.

Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease.

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength.

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na+/H+ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). METHODS: Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. RESULTS: Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. CONCLUSION: Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.

Role of cilia in the pathogenesis of congenital heart disease.

An essential role for cilia in the pathogenesis of congenital heart disease (CHD) has emerged from findings of a large-scale mouse forward genetic screen. High throughput screening with fetal ultrasound imaging followed by whole exome sequencing analysis recovered a preponderance of cilia related genes and cilia transduced cell signaling genes among mutations identified to cause CHD. The perturbation of left-right patterning in CHD pathogenesis is suggested by the association of CHD with heterotaxy, but also by the finding of the co-occurrence of laterality defects with CHD in birth defect registries. Many of the cilia and cilia cell signaling genes recovered were found to be related to Hedgehog signaling. Studies in mice showed cilia transduced hedgehog signaling coordinates left-right patterning with heart looping and differentiation of the heart tube. Cilia transduced Shh signaling also regulates later events in heart development, including outflow tract septation and formation of the atrioventricular septum. More recent work has shown mutations in cilia related genes may also contribute to valve disease that largely manifest in adult life. Overall, these and other findings show cilia play an important role in CHD and also in more common valve diseases.

Brain imaging factors associated with progression of subcortical hyperintensities in CADASIL over 2-year follow-up.

BACKGROUND AND PURPOSE: Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability that is incompletely explained. Early abnormalities in vascular function have been shown in animal models. We postulated that studying changes in vascular function may offer insights into disease progression. METHODS: Twenty-two subjects with CADASIL [50% female, 50 (±11) years] from 19 pedigrees were included in a longitudinal multimodality study using brain magnetic resonance imaging (MRI), clinical measures, neuropsychology and measures of peripheral vascular function. MRI studies included measurement of structural brain changes, cerebral blood flow (CBF) and cerebrovascular reactivity by arterial spin labelling and a CO2 respiratory challenge. RESULTS: Over 2 years, new stroke or transient ischaemic attack (TIA) occurred in five (23%) subjects and new significant disability in one (5%). There were significant increases in number of lacunes, subcortical hyperintensity volume and microbleeds, and a decrease in brain volume. CBF declined by 3.2 (±4.5) ml/100 g/min over 2 years. CBF and carotid-femoral pulse wave velocity at baseline predicted change in subcortical hyperintensity volume at follow-up. Carotid intima-media thickness and age predicted brain atrophy. Baseline CBF was lower in subjects who showed a decline in attention and working memory. CONCLUSIONS: Cerebral blood flow predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADASIL. Over 2 years, there were changes in several relevant imaging biomarkers (CBF, brain volume, lacunes, microbleeds and hyperintensity volume). Future studies in CADASIL should consider assessment of CBF as prognostic factor.

A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development.

The etiology of congenital heart defects (CHDs), which are among the most common human birth defects, is poorly understood because of its complex genetic architecture. Here, we show that two genes implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a receptor-like ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions can arise from biochemical mechanisms that calibrate morphogen signaling strength, a conclusion broadly relevant for the many human diseases in which oligogenic inheritance is emerging as a mechanism for heritability.

The Emergency Medicine Group Standardized Letter of Evaluation as a Workplace-based Assessment: The Validity Is in the Detail.

INTRODUCTION: Interest is growing in specialty-specific assessments of student candidates based on clinical clerkship performance to assist in the selection process for postgraduate training. The most established and extensively used is the emergency medicine (EM) Standardized Letter of Evaluation (SLOE), serving as a substitute for the letter of recommendation. Typically developed by a program's leadership, the group SLOE strives to provide a unified institutional perspective on performance. The group SLOE lacks guidelines to direct its development raising questions regarding the assessments, processes, and standardization programs employ. This study surveys EM programs to gather validity evidence regarding the inputs and processes involved in developing group SLOEs. METHODS: A structured telephone interview was administered to assess the input data and processes employed by United States EM programs when generating group SLOEs. RESULTS: With 156/178 (87.6%) of Accreditation Council of Graduate Medical Education-approved programs responding, 146 (93.6%) reported developing group SLOEs. Issues identified in development include the following: (1) 84.9% (124/146) of programs limit the consensus process by not employing rigorous methodology; (2) several stakeholder groups (nurses, patients) do not participate in candidate assessment placing final decisions at risk for construct under-representation; and (3) clinical shift assessments don't reflect the task-specific expertise of each stakeholder group nor has the validity of each been assessed. CONCLUSION: Success of the group SLOE in its role as a summative workplace-based assessment is dependent upon valid input data and appropriate processes. This study of current program practices provides specific recommendations that would strengthen the validity arguments for the group SLOE.

Quasiperiodic rhythms of the inferior olive.

Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promote rhythmic, synchronized output. However, the interaction of these properties with torrential synaptic inputs in awake behaving animals is not well understood. Here we combine electrophysiological recordings in awake mice with a realistic tissue-scale computational model of the inferior olive to study the relative impact of intrinsic and extrinsic mechanisms governing its activity. Our data and model suggest that if subthreshold oscillations are present in the awake state, the period of these oscillations will be transient and variable. Accordingly, by using different temporal patterns of sensory stimulation, we found that complex spike rhythmicity was readily evoked but limited to short intervals of no more than a few hundred milliseconds and that the periodicity of this rhythmic activity was not fixed but dynamically related to the synaptic input to the inferior olive as well as to motor output. In contrast, in the long-term, the average olivary spiking activity was not affected by the strength and duration of the sensory stimulation, while the level of gap junctional coupling determined the stiffness of the rhythmic activity in the olivary network during its dynamic response to sensory modulation. Thus, interactions between intrinsic properties and extrinsic inputs can explain the variations of spiking activity of olivary neurons, providing a temporal framework for the creation of both the short-term and long-term changes in cerebellar output.

Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine.

Epstein-Barr virus (EBV), a member of the Herpesviridae family, maintains a lifelong latent infection in human B cells. Switching from the latent to the lytic phase of its lifecycle allows the virus to replicate and spread. The viral lytic cycle is induced in infected cultured cells by drugs such as sodium butyrate and azacytidine. Lytic reactivation can be inhibited by natural products and pharmaceuticals. The anticonvulsant drugs valproic acid and valpromide inhibit EBV in Burkitt lymphoma cells. Therefore, other drugs that treat neurological and psychological disorders were investigated for effects on EBV lytic reactivation. Clozapine, an atypical antipsychotic drug used to treat schizophrenia and bipolar disorder, was found to inhibit the reactivation of the EBV lytic cycle. Levels of the viral lytic genes BZLF1, BRLF1, and BMLF1 were decreased by treatment with clozapine in induced Burkitt lymphoma cells. The effects on viral gene expression were dependent on the dose of clozapine, yet cells were viable at an inhibitory concentration of clozapine. One metabolite of clozapine-desmethylclozapine-also inhibited EBV lytic reactivation, while another metabolite-clozapine-N-oxide-had no effect. These drugs may be used to study cellular pathways that control the viral lytic switch in order to develop treatments for diseases caused by EBV.

The effect of pasture quantity temporal variation on milking robot utilization.

In pasture-based automatic milking systems (AMS), a decrease in robot utilization (RU) often occurs in the early morning hours. Novel feeding strategies that encourage voluntary cow traffic throughout 24 h could help mitigate this problem. We determined the effect of 3 distinct pasture allocation methods on RU patterns throughout a 24-h period. The experiment was conducted at the University of Melbourne's Dookie research farm in northern Victoria, Australia. Three Lely Astronaut A3 robotic milking units (Lely, Maassluis, the Netherlands) milked 133 cows, grazing pasture, with concentrate offered at milking in the robots. The farm operated a system of 3-way grazing, with active access to each pasture allocation: 2030-0400 h (allocation A), 0400-1330 h (allocation B), and 1330-2030 h (allocation C). Treatments varied in the quantity of feed offered per hour of active access to each of the 3 pasture allocations. The control treatment offered the same proportion of feed (corrected for active access time) in all 3 pasture allocations (allocation A = 31.3%, B = 39.6%, and C = 29.2%). The day treatment offered the largest proportion of feed during the day (allocation A = 20%, B = 40%, and C = 40%), following the cows' diurnal pattern of feeding activity. The night treatment offered the largest proportion of feed at night (allocation A = 42%, B = 40%, and C = 18%). Due to the nature of pasture-based AMS, treatments could not be applied simultaneously. Therefore, treatments were applied to the entire herd and repeated twice over 42 d, lasting 7 d/treatment, with the first 3 d for habituation, followed by 4 d of data collection. Robot utilization (milkings/h) varied throughout 24 h between treatments, with the night treatment recording greater RU at 0800, 1800, and 1900 h and lower RU between 2100 to 0100 h, compared with the day treatment. The proportion of the herd milking between 0000 and 0600 h was greater for the control (43.3%) and day (45.3%) treatments compared with the night treatment (25.8%). Herd-average daily pasture intake was similar (10.5 kg of dry matter) for all treatments. This experiment is the first to demonstrate the manipulation of RU by varying the quantity of pasture offered. However, the use of variable allocation alone did not eliminate the decrease in RU between 0000 and 0600 h, with the timing of allocation also likely to play a role. We recommend a further research focus on combining both timing and quantity of pasture allocated to improve RU in pasture-based AMS.

When the Learner Is the Expert: A Simulation-Based Curriculum for Emergency Medicine Faculty.

Emergency physicians supervise residents performing rare clinical procedures, but they infrequently perform those procedures independently. Simulation offers a forum to practice procedural skills, but simulation labs often target resident learners, and barriers exist to faculty as learners in simulation-based training. Simulation-based curricula focused on improving emergency medicine (EM) faculty's rare procedure skills were not discovered on review of published literature. Our objective was to create a sustainable, simulation-based faculty education curriculum for rare procedural skills in EM. Between 2012 and 2019, most EM teaching faculty at a single, urban, Level 1 trauma center completed an annual two-hour simulation-based rare procedure lab with small-group learning and guided hands-on instruction, covering 30 different procedural education sessions for faculty learners. A questionnaire administered before and after each session assessed EM faculty physicians' self-perceived ability to perform these rare procedures. Participants' self-reported confidence in their performance improved for all procedures, regardless of prior procedural experience. Faculty participation was initially mandatory, but is now voluntary. Diverse strategies were used to address barriers in this learner group including eliciting learner feedback, offering continuing medical education credits, gradual roll-out of checklist assessments, and welcoming expertise of faculty leaders from EM and other specialties and professions. Participants perceived training to be most helpful for the most rarely-encountered clinical procedures. Similar curricula could be implemented with minimal risk at other institutions.

Comparing embodiment experiences in expert meditators and non-meditators using the rubber hand illusion.

One assessment of embodiment is the rubber hand illusion (RHI), a visuo-tactile illusion in which individuals attribute a sense of ownership to a rubber hand and disownership to their real hand. Interestingly, interoception seems to influence RHI susceptibility. In this study, we administered the RHI and the Multidimensional Assessment of Interoceptive Awareness (MAIA) to examine embodiment experiences and interoceptive awareness in experienced meditators (n = 15) and non-meditators (n = 15). We found that meditators reported less intensity in rubber hand ownership, but there was no significant difference between groups with respect to disownership of their real hand or drift in finger proprioception. Moreover, we found, from our MAIA results, that disownership experiences were associated with a feeling of trusting one's body in non-meditators and with the ability to maintain attention to unpleasant bodily sensations in meditators. These results suggest a unique relationship between interoceptive awareness and embodiment related to meditation.

Early Trajectory Prediction in Elite Athletes.

Cerebellar plasticity is a critical mechanism for optimal feedback control. While Purkinje cell activity of the oculomotor vermis predicts eye movement speed and direction, more lateral areas of the cerebellum may play a role in more complex tasks, including decision-making. It is still under question how this motor-cognitive functional dichotomy between medial and lateral areas of the cerebellum plays a role in optimal feedback control. Here we show that elite athletes subjected to a trajectory prediction, go/no-go task manifest superior subsecond trajectory prediction accompanied by optimal eye movements and changes in cognitive load dynamics. Moreover, while interacting with the cerebral cortex, both the medial and lateral cerebellar networks are prominently activated during the fast feedback stage of the task, regardless of whether or not a motor response was required for the correct response. Our results show that cortico-cerebellar interactions are widespread during dynamic feedback and that experience can result in superior task-specific decision skills.

Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.

Limited impact of awareness-raising campaigns on hepatitis C testing practices among general practitioners.

The global hepatitis strategy calls for increased effort to diagnose those infected, with a target of 90% diagnosed by 2030. Scotland's Action Plan on Hepatitis C included awareness-raising campaigns, undertaken during 2008-2011, to promote testing by general practitioners. We examined hepatitis C virus (HCV) testing practice among general practitioners before and following these campaigns. Scottish general practitioners were surveyed, using Dillman's method, in 2007 and 2013; response rates were 69% and 60%, respectively. Most respondents offer testing when presented with a risk history (86% in 2007, 88% in 2013) but only one-fifth actively sought out risk factors (19% in 2007, 21% in 2013). Testing was reportedly always/almost always/usually offered to people who inject drugs (84% in 2007, 87% in 2013). Significant improvements in the offer of testing were reported in patients with abnormal LFTs (41% in 2007, 65% in 2013, P<.001) and who had received medical/dental treatment in high prevalence countries (14% in 2007, 24% in 2013, P=.001). In 2013, 25% of respondents had undertaken HCV-related continued professional development. This group was significantly more likely to actively seek out risk factors (P=.009) but only significantly more likely to offer a test to patients who had received medical/dental treatment in high prevalence countries (P=.001). Our findings suggest that government-led awareness raising campaigns have limited impact on general practitioners' testing practices. If the majority of the HCV-infected population are to be diagnosed, practitioner-based or physician-centred interventions should be considered alongside educational initiatives targeted at professionals.

The 'cognitive footprint' of psychiatric and neurological conditions: cross-sectional study in the UK Biobank cohort.

OBJECTIVE: We aimed to quantify the prevalence of cognitive impairment in adults with a history of mood disorder, schizophrenia, multiple sclerosis or Parkinson's disease, within a large general population cohort. METHOD: Cross-sectional study using UK Biobank data (n = 502 642). Psychiatric and neurological exposure status was ascertained via self-reported diagnoses, hospital records and questionnaires. Impairment on reasoning, reaction time and memory tests was defined with reference to a single unexposed comparison group. Results were standardised for age and gender. Sensitivity analyses examined the influence of comorbidity, education, information sources and missing data. RESULTS: Relative to the unexposed group, cognitive impairment was least common in major depression (standardised prevalence ratios across tests = 1.00 [95% CI 0.98, 1.02] to 1.49 [95% CI 1.24, 1.79]) and most common in schizophrenia (1.89 [95% CI 1.47, 2.42] to 3.92 [95% CI 2.34, 6.57]). Prevalence in mania/bipolar was similar to that in multiple sclerosis and Parkinson's disease. Estimated population attributable prevalence of cognitive impairment was higher for major depression (256 per 100 000 [95% CI 130, 381]) than for all other disorders. CONCLUSION: Although the relative prevalence of cognitive impairment was lowest in major depression, the population attributable prevalence was highest overall for this group.