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High-performance quantum memories are an essential component for regulating temporal events in quantum networks. As a component in quantum-repeaters, they have the potential to support the distribution of entanglement beyond the physical limitations of fiber loss. This will enable key applications such as quantum key distribution, network-enhanced quantum sensing, and distributed quantum computing. Here, we present a quantum memory engineered to meet real-world deployment and scaling challenges. The memory technology utilizes a warm rubidium vapor as the storage medium, and operates at room temperature, without the need for vacuum- and/or cryogenic- support. We demonstrate performance specifications of high-fidelity retrieval (95\%) and low operation error $(10^{-2})$ at a storage time of 160 $\mu s$ for single-photon level quantum memory operations. We further show a substantially improved storage time (with classical-level light) of up to 1 ms by suppressing atomic diffusions. The device is housed in an enclosure with a standard 2U rackmount form factor, and can robustly operate on a day scale in a noisy environment. This result marks an important step toward implementing quantum networks in the field., Comment: 16 pages, 10 figures

We present our work on the development of a bichromatic photon source based on warm atomic vapors. This entanglement source is capable of directly interfacing with telecom networks as well as atomic quantum memories.

Long-range Rydberg interactions, in combination with electromagnetically induced transparency (EIT), give rise to strongly interacting photons where the strength, sign, and form of the interactions are widely tunable and controllable. Such control can be applied to both coherent and dissipative interactions, which provides the potential to generate novel few-photon states. Recently it has been shown that Rydberg-EIT is a rare system in which three-body interactions can be as strong or stronger than two-body interactions. In this work, we study a three-body scattering loss for Rydberg-EIT in a wide regime of single and two-photon detunings. Our numerical simulations of the full three-body wavefunction and analytical estimates based on Fermi's Golden Rule strongly suggest that the observed features in the outgoing photonic correlations are caused by the resonant enhancement of the three-body losses., 6 pages, 4 figures

Rydberg polaritons provide an example of a rare type of system where three-body interactions can be as strong or even stronger than two-body interactions. The three-body interactions can be either dispersive or dissipative, with both types possibly giving rise to exotic, strongly-interacting, and topological phases of matter. Despite past theoretical and experimental studies of the regime with dispersive interaction, the dissipative regime is still mostly unexplored. Using a renormalization group technique to solve the three-body Schr\"odinger equation, we show how the shape and strength of dissipative three-body forces can be universally enhanced for Rydberg polaritons. We demonstrate how these interactions relate to the transmission through a single-mode cavity, which can be used as a probe of the three-body physics in current experiments., Comment: 6+6 pages, 4 figures

Single photons coupled to atomic systems have shown to be a promising platform for developing quantum technologies. Yet a bright on-demand, highly pure, and highly indistinguishable single-photon source compatible with atomic platforms is lacking. In this work, we demonstrate such a source based on a strongly interacting Rydberg system. The large optical nonlinearities in a blockaded Rydberg ensemble convert coherent light into a single collective excitation that can be coherently retrieved as a quantum field. We simultaneously observe a fully single-mode (spectral, temporal, spatial, and polarization) efficiency up to 0.098(2), a detector-background-subtracted g ( 2 ) = 5.0 ( 1.6 ) × 10 − 4 , and indistinguishability of 0.980(7), at an average photon production rate of 1.18 ( 2 ) × 10 4 s − 1 . All of these make this system promising for scalable quantum information applications. Furthermore, we investigate the effects of contaminant Rydberg excitations on the source efficiency and observed single-mode efficiencies up to 0.18(2) for lower photon rates. Finally, recognizing that many quantum information protocols require a single photon in a fully single mode, we introduce metrics that take into account all degrees of freedom to benchmark the performance of on-demand sources.

Ultracold systems offer an unprecedented level of control of interactions between atoms. An important challenge is to achieve a similar level of control of the interactions between photons. Towards this goal, we propose a realization of a novel Lennard-Jones-like potential between photons coupled to the Rydberg states via electromagnetically induced transparency (EIT). This potential is achieved by tuning Rydberg states to a F\"orster resonance with other Rydberg states. We consider few-body problems in 1D and 2D geometries and show the existence of self-bound clusters (``molecules'') of photons. We demonstrate that for a few-body problem, the multibody interactions have a significant impact on the geometry of the molecular ground state. This leads to phenomena without counterparts in conventional systems: For example, three photons in two dimensions preferentially arrange themselves in a line configuration rather than in an equilateral-triangle configuration. Our result opens a new avenue for studies of many-body phenomena with strongly interacting photons.

People’s differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal–numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal–numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer’s disease and schizophrenia.

Advances in the distribution of quantum information will likely require entanglement shared across a hybrid quantum network. Many entanglement protocols require the generation of indistinguishable photons between the various nodes of the network. This is challenging in a hybrid environment due to typically large differences in the spectral and temporal characteristics of single photons generated in different systems. Here we show, for the first time, quantum interference between photons generated from a single atomic ion and an atomic ensemble, located in different buildings and linked via optical fibre. Trapped ions are leading candidates for quantum computation and simulation with good matter-to-photon conversion. Rydberg excitations in neutral-atom ensembles show great promise as interfaces for the storage and manipulation of photonic qubits with excellent efficiencies. Our measurement of high-visibility interference between photons generated by these two, disparate systems is an important building block for the establishment of a hybrid quantum network.

Following publication of this article, the authors noticed an error in Supplementary Table 1. In the original Supplementary Table 1, one of the criteria for control participants was incorrectly given as ‘Report extensive recent symptoms of depression: less than 14 on summed response (where “not at all” = 1 and “nearly every day” = 4) to recent’. This has now been corrected to: ‘Report extensive recent symptoms of depression: less than 5 on summed response (where “not at all” = 1 and “nearly every day” = 4) to recent’.

TNF-α-inhibitors are known to induce skin adverseeffects including psoriasis and alopecia areata. Here, wedescribe a unique pattern of hair loss that has psoriaticand alopecia areata-like features. Diagnosis requiresclinical-pathologic correlation and is supportedby increased catagen/telogen hairs, psoriasiformepidermal hyperplasia, perifollicular lymphocyticinfiltrate, and the presence of eosinophils and plasmacells. Although there are no treatment consensusguidelines, management options include stoppingtherapy, switching to a different TNF-α inhibitor orustekinumab (in severe cases), or continuing TNF-αinhibitor therapy with addition of topical, intralesional,or systemic immunosuppressants.

Aims:To assess the comorbidity rates of alcohol use disorders (AUDs) in bipolar disorder (BD) and to explore possible sources of heterogeneity.Methods:Studies were identified through database searches. Meta-analytic techniques were employed to aggregate data on lifetime comorbidity and to explore possible sources of heterogeneity. Funnel plots were used to detect publication bias.Results:In clinical studies, AUDs affected more than one in three subjects with BD. Significant heterogeneity was found, which was largely explained by the geographical location of study populations and gender ratio of participants. AUDs affected more than one in five women and two in five men.Conclusion:AUDs are highly prevalent in BD. Our study revealed a substantial heterogeneity across studies. Further research including control groups is needed. Patients with BD should be assessed for current and previous AUDs.

Background: Hamstring strains are one of the most common injuries in sport. Previous injury has been found to be one of the greatest risk factors associated with recurrent hamstring strains. Although rehabilitation programmes have been developed and implemented to aid safe and efficient return-to-play, the incidence of hamstring injuries has not decreased. Discussion: As hamstring strains most commonly occur during the eccentric phase of muscle action, rehabilitation should focus on eccentric muscle strengthening. The L-protocol and the Nordic Hamstring Exercise protocol strengthen the hamstring muscles eccentrically. They have been found to be effective in decreasing the incidence of new hamstring strains as well as the rate of recurrence. This commentary therefore aims to suggest changes to the return-to-play criteria following hamstring strains to prevent the seemingly unpreventable.

TNF-α-inhibitors are known to induce skin adverseeffects including psoriasis and alopecia areata. Here, wedescribe a unique pattern of hair loss that has psoriaticand alopecia areata-like features. Diagnosis requiresclinical-pathologic correlation and is supportedby increased catagen/telogen hairs, psoriasiformepidermal hyperplasia, perifollicular lymphocyticinfiltrate, and the presence of eosinophils and plasmacells. Although there are no treatment consensusguidelines, management options include stoppingtherapy, switching to a different TNF-α inhibitor orustekinumab (in severe cases), or continuing TNF-αinhibitor therapy with addition of topical, intralesional,or systemic immunosuppressants.

IntroductionFor women with bipolar disorder, childbirth is a high-risk period with 40–50% experiencing a recurrence and 20% developing a severe episode of postpartum psychosis. Bipolar episodes in the perinatal period affect women and their families.Managing bipolar disorder in pregnancy and postpartum is a challenge. There is lack of literature to inform that and an urgent need for more data.ObjectivesTo develop and validate a risk prediction model for individual prognosis of the risk of recurrence of bipolar disorder for women in the perinatal period.AimsTo provide evidence-based information to help women and the clinicians that look after them make decisions about their care, taking into account the most recent scientific knowledge and their individual characteristics.MethodsThe development of the model will be done in retrospective data from a large clinical cohort from the Bipolar Disorder Research Network (BDRN.org). The validation will be done in a prospectively recruited sample.Participants will be 2181 parous women with a lifetime diagnosis of bipolar disorder from BDRN and 300 prospectively recruited pregnant women with a history of postpartum psychosis or bipolar disorder.Predictors will be chosen based on clinical experience and literature, from data collected via semi-structured interview (in pregnancy and 3 months postpartum, medical and psychiatric notes) e.g. medication, smoking, parity, obstetric complications and sleep.ResultsN/A.ConclusionsWe will present the full prediction model (regression coefficients and model intercept) and report performance measures (with CIs).We will discuss its potential clinical use and implications for future research.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Summary“Schizoaffective” refers to a mix of clinical features associated with prototypical schizophrenia and prototypical bipolar disorder. Such cases are common but definitions have varied substantially. Nosological possibilities considered include (a) a form of schizophrenia, (b) a form of mood disorder, (c) a distinct disorder, (d) some mixture of (a)-(c). In current usage “schizoaffective disorder” tends to be used only when cases cannot be fitted to definitions of schizophrenia or bipolar disorder and such cases have been under-represented in cases collections to date. Methodological and practicalissues continue to cause difficulty for accumulating robust knowledge about schizoaffectivedisorder. Here we consider genetic understanding of schizoaffective disorder, particularly recent findings. These show that bipolar disorder andschizophrenia are not completely separate disease entities and confirm that schizoaffectivedisorder is genetically related to both. Some genetic variants influencerisk broadly across the mood-psychosis spectrum (e.g. Variation at CACNA1C). Some studies have implicated common variation at specific genes and gene families as conferring relatively specific phenotypic risk for a schizoaffective-type clinical pattern (e.g. GABAA receptorgenes). Such findings are of great interest and offer promise ofgreat advances in understanding over the next 20 years. It is important that there is a willingnessof researchers to study schizoaffective cases and to use approaches to phenotypic assessmentand classification that go beyond the traditional approaches enshrined within DSM and ICD.

We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted.

Gene x environment (G x E) interactions are increasingly thought to have substantial influence on the aetiology and clinical manifestations of complex disorders. In ADHD, although main effects of specific genetic variants and pre- or peri-natal variables have been reported and replicated using pooled analyses, few studies have looked at possible interactions. In a clinical sample of 266 children with ADHD, we tested for interaction between gene variants (in DRD4, DAT1, DRD5, and 5HTT) found to be associated with ADHD in pooled analyses and maternal smoking, alcohol use during pregnancy and birth weight. First, G x E effects on a diagnosis of ADHD were tested using conditional logistic regression analyses. Second, possible modifying effects of G x E on symptoms of associated conduct disorder and oppositional defiant disorder (ODD) were investigated using linear regression analysis. The sample size associated with each of the analyses differed as not each variant had been genotyped for each individual. No effects of G x E on ADHD diagnosis were observed. The results suggest that lower birth weight and maternal smoking during pregnancy may interact with DRD5 and DAT1 (birth weight only) in influencing associated antisocial behavior symptoms (ODD and conduct disorder). These preliminary findings showed no evidence of interaction between previously implicated variants in ADHD and specific environmental risk factors, on diagnosis of the disorder. There may be evidence of G x E on associated antisocial behavior in ADHD, but further investigation is needed.

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. Refereed/Peer-reviewed

Background Bipolar disorder (BD) includes a broad range of phenotypic features – most research examining its genetic underpinning focuses on the overall syndrome rather than its subphenotypic components. BD is a highly heritable disorder and while its genetic architecture is not fully elucidated there is increasingly strong support for a very polygenic component with partial polygenic overlap with schizophrenia (SZ). Here we present preliminary results from an analysis examining the association of SZ derived polygenic risk scores (PRS) across different BD subtypes (Bipolar Type 1(BPI), Bipolar Type 2 (BPII) and Schizoaffective disorder (SAD), and subphenotypes defined by the presence of psychosis and its associated level of mood incongruence. Methods We used a UK sample of 3101 BP cases, collected using a consistently administrated interview protocol with OPCRIT confirmed lifetime diagnosis of Research Diagnostic Criteria (RDC - BPI, BPII or SAD). PRS were generated using 1000 genomes (phase3, 2014) imputed genetic data (INFO score>0.8, HWE>1e-6, MAF>0.01) trained on the results from Psychiatric Genetic Consortium (PGC2) SZ GWAS, pruned r2 Results PRS with the SZ association p-value cut-off of 0.5, have shown significant association across the BD subtypes with relative risk ratios RRR = 1.28 (95%CI: 1.18-1.39, p Discussion Preliminary analyses show a genetic - phenotypic association, between polygenic features of schizophrenia and BP characterised by the presence of psychosis, suggesting the phenotypic overlap between SZ and BD may in part be driven by polygenic overlap. This finding is further supported by the association of PRS and level of mood incongruence in the content of psychotic symptoms. These results suggest the PRS effect is not solely mediated though the psychosis subphenotype, at least in the BPI group. Our analyses show promise for the strategy of examining polygenic/phenotypic associations based on fine grained clinical characterisations

Approximately 25% of patients with hemophilia A develop inhibitory antibodies after treatment with factor VIII. Most of the inhibitory activity is directed against epitopes in the A2 and C2 domains. Anti-A2 inhibitory antibodies recognize a 25-residue segment bounded by R484-I508. Several antigenic residues in this segment have been identified, including R484, R489, and P492. The immunogenicity of purified recombinant B domain–deleted (BDD) human factor VIII molecules containing mutations at R484A/R489A or R484A/R489A/P492A was studied in hemophilia A mice. Inhibitory antibody titers in mice receiving the R484A/R489A/P492A mutant, but not the R484A/R489A mutant, were significantly lower than in mice receiving control human BDD factor VIII. The specific coagulant activity and the in vivo clearance and hemostatic efficacy in hemophilia A mice of the R484A/R489A/P492A mutant were indistinguishable from human BDD factor VIII. Thus, the inhibitory antibody response to human factor VIII can be reduced by mutagenesis of a B-cell epitope without apparent loss of function, suggesting that this approach may be useful for developing a safer form of factor VIII in patients with hemophilia A.

Hyate is a commercial plasma-derived porcine factor (F)VIII concentrate that is used in the treatment of patients with inhibitory antibodies to FVIII. OBI-1 is a recombinant B domain-deleted form of porcine FVIII that is in clinical development for the same indication. Hemophilia A mice were presensitized with human FVIII to simulate clinical inhibitory antibody formation and then were randomized to receive OBI-1 or Hyate:C in a comparative immunogenicity trial. OBI-1 or Hyate:C were given in a series of four intravenous injections at weekly intervals at doses of 1, 10, or 100 U kg(-1). Inhibitory antibodies to porcine FVIII were not detected by Bethesda assay in most of the mice given OBI-1 or Hyate:C at doses of 1 or 10 U kg(-1), but were identified in 81% and 94% of mice given 100 U kg(-1) of OBI-1 or Hyate:C, respectively. There was no significant difference between OBI-1 and Hyate:C in inhibitory antibody formation at any dose, although there was a trend toward a lower Bethesda titer in OBI-1-treated mice at 10 U kg(-1) (P = 0.09). Total anti-FVIII antibodies to Hyate:C and OBI-1 were also measured by ELISA using immobilized purified plasma-derived porcine FVIII and OBI-1, respectively, as antigens. At the 10 and 100 U kg(-1) doses, the mean anti-FVIII response was higher in Hyate:C-treated-mice than in OBI-1-treated mice (P = 0.02 and P = 0.004, respectively). The results using this model suggest that OBI-1 may be less immunogenic and safer than Hyate:C in FVIII inhibitor patients.

A relatively new analytical instrument for the measurement of 5-day biochemical oxygen demand (BOD 5 ), chemical oxygen demand, total suspended solids (TSS), total organic carbon (TOC), nitrates and surfactants has been developed commercially. It is based on the use of ultraviolet spectrophotometry and a deterministic approach to analyze the sample's spectrum by comparing it with a series of historical reference spectra. Using standard methods for the measurement of BOD 5 , TSS and TOC as true values, the use of this instrument was evaluated. The samples tested were obtained from both wastewater and water treatment facilities. Results indicate that the BOD 5 measurement performed best. There was no correlation found for TSS or TOC.

Fulminant hepatic failure (FHF) in humans produces a bleeding diathesis due in large part to a reduction in the biosynthesis of liver-derived coagulation factors. Remarkably, factor VIII procoagulant activity is elevated in most of these patients despite widespread liver cell death. FHF can be modeled in mice by administration of azoxymethane, the active ingredient found in cycad palm nuts. We compared the expression of factor VIII to other hepatic hemostatic factors in azoxymethane-induced murine FHF. Mice displayed dose-dependent decreases in all coagulation factor activities measured, including factors V, VII, VIII, and IX. At the highest dose of azoxymethane (50 μg/g body weight), factor VIII activity in plasma decreased by 98% within 36 hours after treatment, which was associated with an 80% reduction in hepatic factor VIII messenger RNA (mRNA). In contrast, factor VIII mRNA levels in spleen, kidney, and lung tissue of azoxymethane-treated mice were unchanged. Cellular damage in these mice appeared to be limited to hepatocytes as evident by histologic examination. This finding is supported by 2 observations. First, hepatic mRNA levels of von Willebrand factor, which is synthesized by liver sinusoidal endothelial cells but not hepatocytes, were unchanged. Second, von Willebrand factor was detected antigenically in liver sections of azoxymethane-treated mice by immunofluorescence. These results indicate that the contribution of the liver to factor VIII biosynthesis is not replaced or significantly supplemented by other tissues in this model of FHF.

SummaryHemophilia A is the inherited bleeding disorder that results from mutation of blood coagulation factor VIII (fVIII). Described here is the generation of a regulated expression system producing recombinant murine fVIII. Murine B-domainless fVIII was expressed at a peak level of 4 units/106 cells/24 h in serum-free media. Subsequently, a two-step purification procedure resulted in 5,300-fold enrichment and a 70% yield. Highly purified recombinant murine fVIII had a specific coagulant activity of 660 units per nanomole. It underwent proteolytic processing by thrombin to yield an activated heterotrimer that demonstrated significantly greater stability than activated human fVIII. Recombinant murine fVIII was utilized to generate an anti-fVIII polyclonal antibody. Intravenous injection of recombinant murine fVIII into hemophilia A mice failed to induce a significant anti-fVIII immune response using a schedule that yielded high titer inhibitory antibodies to human fVIII. This may provide an important model for the study of immune tolerance to fVIII.

IntroductionThe perinatal period is a high-risk period for the development of illness episodes in women with bipolar disorder. Relapse rates vary between 9 and 75% depending on the study. The overall risk of a severe episode is approximately 20%. The impact on women, the relationships with their babies and their families can be devastating. In the UK costs to society are £8.1 billion per year-cohort of births. The advice currently given to women is based of general risk rates. Women's needs of information for decision-making in the perinatal period are not being met.ObjectivesTo review the risk prediction approaches used for women with bipolar disorder in the perinatal period.AimsTo understand the existing risk prediction models and approaches used for prognosis of the risk of recurrence of bipolar disorder for women in the perinatal period.MethodsSystematic literature search of public medical electronic databases and grey literature on risk prediction for bipolar episodes in the perinatal period.ResultsWe will present the existing models and approaches used for risk prediction of illness episodes in the perinatal period.ConclusionsAwareness of existing risk prediction models for recurrence of bipolar disorder in the perinatal period will allow better informed risk-benefit analysis of treatment and management options.This person-centred approach will help women and clinicians in their decision-making at this crucial high-risk period.Disclosure of interestThe authors have not supplied their declaration of competing interest.

BackgroundThe relative contribution of demographic, lifestyle and medication factors to the association between affective disorders and cardiometabolic diseases is poorly understood.AimsTo assess the relationship between cardiometabolic disease and features of depresion and bipolar disorder within a large population sample.MethodCross-sectional study of 145 991 UK Biobank participants: multivariate analyses of associations between features of depression or bipolar disorder and five cardiometabolic outcomes, adjusting for confounding factors.ResultsThere were significant associations between mood disorder features and ‘any cardiovascular disease’ (depression odds ratio (OR) = 1.15, 95% CI 1.12–1.19; bipolar OR = 1.28, 95% CI 1.14–1.43) and with hypertension (depression OR = 1.15, 95% CI 1.13–1.18; bipolar OR = 1.26, 95% CI 1.12–1.42). Individuals with features of mood disorder taking psychotropic medication were significantly more likely than controls not on psychotropics to report myocardial infarction (depression OR = 1.47, 95% CI 1.24–1.73; bipolar OR = 2.23, 95% CI 1.53–3.57) and stroke (depression OR = 2.46, 95% CI 2.10–2.80; bipolar OR = 2.31, 95% CI 1.39–3.85).ConclusionsAssociations between features of depression or bipolar disorder and cardiovascular disease outcomes were statistically independent of demographic, lifestyle and medication confounders. Psychotropic medication may also be a risk factor for cardiometabolic disease in individuals without a clear history of mood disorder.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. © 2014 The Author.

Micromechanical models for the prediction of the longitudinal strength of metal-matrix composites are often based on one constituent reaching its elastic limit. This procedure can grossly underestimate the useful or effective strength of the composite. At elevated temperatures, the yield strength of the matrix material can become very low relative to the strength of the fiber (in extreme cases as low as 5-10 % of the fiber value). Even though the matrix has yielded, further load can be carried by the fibers. The problem can be further complicated by the formation of a third phase or a reaction zone between the matrix and the fiber. The fact that this reaction zone has distinct material properties must be accounted for in any analysis. To get a valid picture of the composite's true load carrying ability the complete elastic-plastic stress-strain behavior must be studied. This paper presents results of such analyses for a system with a monotonically increasing load up to failure of the first constituent. The three constituents are modeled as strain-hardening materials. Results are first obtained for a simple bilinear model of the stress-strain be havior in each material. A more detailed study was also conducted in which the three materials were modeled with curvilinear post-yield behavior. Results are presented for some representative constituent material properties. These results indicate the methods of analyses outlined in this paper are valid and easy to use. The results also clearly show that the entire elastic-plastic stress-strain behavior of the metal-matrix composite is more im portant than simply determining the initial yielding of one component. Strength predic tions based on the first component yielding are seen to be often far too conservative.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

The bending behavior of graphite-epoxy I-beams was examined. The beams used in this study were made of T 300 934 graphite-epoxy with three different layups. Short-beam shear tests, using three-point bending, were used. The shear-deflection and bending-deflection contributions were separated using Timoshenko Beam Theory. The equivalent bending stiffness was obtained from the deflection due to bending. The bending stiffness was calculated in two ways: using a method based on lamination theory, and using a transformed-section method developed especially for composites. A comparison of analytical and experimental results indicates that both methods are accurate tools for predicting the bending stiffness of composite material beams.

Darier disease (DD) is a rare autosomal dominantly inherited skin disorder in which co-occurrence of neuropsychiatric abnormalities has been frequently reported by dermatologists. It is caused by mutations in a single gene, ATP2A2, which is expressed in the skin and brain.To conduct the first systematic investigation of the neuropsychiatric phenotype in DD.One hundred unrelated individuals with DD were assessed using a battery of standardized neuropsychiatric measures. Data were also obtained on a number of clinical features of DD.Individuals with DD were found to have high lifetime rates of mood disorders (50%), specifically major depression (30%) and bipolar disorder (4%), and suicide attempts (13%) and suicidal thoughts (31%). These were more common in DD when compared with general population data. The prevalence of epilepsy (3%) in the sample was also higher than the prevalence in the general population. There was no consistent association of specific dermatological features of DD and presence of psychiatric features.These findings highlight the need for clinicians to assess and recognize neuropsychiatric symptoms in DD. The results do not suggest that neuropsychiatric symptoms are simply a psychological reaction to having a skin disease, but are consistent with the pleiotropy hypothesis that mutations in the ATP2A2 gene, in addition to causing DD, confer susceptibility to neuropsychiatric features. Further research is needed to investigate genotype-phenotype correlations between the types and/or locations of pathogenic mutations within ATP2A2 and the expressed neuropsychiatric phenotypes.

Strong evidence that rare variants of relatively high penetrance are involved in the etiology of schizophrenia is currently restricted to the data from studies investigating copy number variants and major structural re-arrangements in that disorder. Global tests of the hypothesis of the involvement of fairly high penetrance rare single nucleotide changes or small insertion deletion events await the genesis of data from large-scale sequencing studies, meanwhile, a pragmatic approach to trying to detect such alleles is to target sequencing efforts on genes for which there is compelling evidence from other sources for their involvement in this disorder. We have undertaken a study, which aimed to identify whether rare (frequency ∼0.001%) coding variants in the schizophrenia susceptibility gene ZNF804A are involved in this disorder. We screened the coding regions of the gene in 517 schizophrenic cases and 501 controls, and genotyped rare non-synonymous variants in a case-control sample powered to detect association to rare alleles with an effect size (odds ratio) of 5. No single rare variant was associated with schizophrenia, nor was the burden of rare, or even fairly common, non-synonymous variants. Our results do not support the hypothesis that moderately rare non-synonymous variants at the ZNF804A locus are involved in schizophrenia susceptibility. © 2010 Wiley-Liss, Inc.

This paper describes modifications to a finite element solution for the wide angle parabolic equation (PE). The modifications to the PE allow the computationally efficient solution of the problem of sound propagation over ground whose impedance varies with range. In particular, the set of linear algebraic equations that propagate the field outward in range is solved with a UL (upper, lower triangular) decomposition, instead of the standard LU (lower, upper triangular) scheme. This approach allows the change in impedance to affect only a single element in the decomposition. Consequently, all previous calculations in the decomposition can be saved in proceeding from one range step to the next. Results are presented for several cases, in which the ground suffers an abrupt change in acoustic impedance at some distance along the propagation path. Comparisons to existing experimental data are made and the method presented here matches the published data quite well. Other diffraction cases are presented for whic...

We present a method for testing overrepresentation of biological pathways, indexed by gene-ontology terms, in lists of significant SNPs from genome-wide association studies. This method corrects for linkage disequilibrium between SNPs, variable gene size, and multiple testing of nonindependent pathways. The method was applied to the Wellcome Trust Case-Control Consortium Crohn disease (CD) data set. At a general level, the biological basis of CD is relatively well known for a complex genetic trait, and it thus acted as a test of the method. The method, known as ALIGATOR (Association LIst Go AnnoTatOR), successfully detected biological pathways implicated in CD. The method was also applied to a meta-analysis of bipolar disorder, and it implicated the modulation of transcription and cellular activity, including that which occurs via hormonal action, as an important player in pathogenesis.

Traditionally in genetic case-control studies controls have been screened to exclude subjects with a personal history of illness. This control group has the advantage of optimal power to detect loci involved in illness, but requires more work and may incur substantial cost in recruitment. An alternative approach to screening is to use unscreened controls sampled from the general population. Such controls are generally plentiful and inexpensive, but in general there is a risk that some may have the same disease as the cases, which will reduce power to detect associations. We have quantified the extent of this power loss, and produced mathematical formulae for the number of unscreened controls necessary to achieve the same power as a fixed sample of screened controls. The effect of using unscreened controls will also depend on the ratio of the number of screened controls to cases specified in the original study design, and this is also investigated. We have also investigated the cost-benefits of the screened and unscreened approaches, according to variation in the relative costs of sampling screened and unscreened controls, together with genotyping costs. We have, thus, identified the range of situations in which using unscreened controls is a cost-effective alternative to the screened control method and could be considered when designing a study. In many of the typical, real-world situations in complex genetics, the use of unscreened controls is potentially cost-effective and can, in general, be considered for disorders with population prevalence Kp < 0.2. With the steady reduction in genotyping costs and the availability of common sets of “population controls” this design is likely to become increasingly cost effective.

Edited by M Leboyer and F Bellivier. Totowa, NJ: Humana Press, 2003, £82.50 (US$99.50), pp 268. ISBN 1588290379 This book is timely. Psychiatric genetics, which is one of the most challenging areas of medical genetics, currently offers enormous opportunities to improve the understanding of mental illness and the practice of clinical psychiatry. Phenotypic issues are, of course, important in all aspects of complex genetics, and within psychiatric genetics issues of phenotype definition and measurement are crucial. Major molecular genetic investigations using both positional and candidate approaches have been ongoing for several of the major psychiatric disorders over the last 10 or 15 years. Early successes, of …

To examine whether variation at two common polymorphisms, T102C and -1438AG, of the serotonin 2A gene (5HT2A) are involved in the puerperal triggering mechanism of bipolar affective puerperal psychosis.A total of 242 parous women diagnosed with bipolar disorder were genotyped for the two polymorphisms. Of these, 165 women had experienced a manic or psychotic episode, according to DSM-IV criteria, within 6 weeks of childbirth (the puerperal psychosis group). The comparison group comprised of 77 parous women who had not experienced psychiatric disturbance following childbirth.No significant differences between genotype or allelic frequencies were found between the two groups for either polymorphism.The results indicate that variation at two common polymorphisms of the 5HT2A gene does not appear to play a major role in the development of bipolar affective puerperal psychosis.

Dopa decarboxylase (DDC) catalyses the synthesis of both dopamine and serotonin as well as trace amines suggested to possess neuromodulating capabilities. We have previously reported evidence suggesting an association between DDC and bipolar affective disorder (BPAD) [Børglum et al., 1999]. To further investigate the possible role of DDC in BPAD, we analyzed a 1- and a 4-bp deletion variant-both of putative functional significance-in two new samples: a case-control sample with 140 cases and 204 controls, and 100 case-parents trios. We also tested for association in subjects with familial disease in both the new and the previously investigated samples. The previously reported association was not replicated in either of the new samples. However, a preponderance of the 1-bp deletion was increased by analysis of the familial cases separately for all case-control samples investigated, indicating a possible association with familial disease (combined analysis, P = 0.02). In the trio sample, a preferential paternal transmission of the 4-bp deletion was observed (P = 0.006). DDC is located next to the imprinted gene GRB10, which is expressed specifically from the paternal allele in fetal brains. Increased transmission of paternal DDC alleles has also been suggested in attention deficit hyperactivity disorder. We suggest that DDC might confer susceptibility to BPAD predominantly when paternally transmitted.