Proportion and characteristics of young people in a first-episode psychosis clinic who first attended an at-risk mental state service or other specialist youth mental health service.

BACKGROUND: Services for young people identified as having an 'at-risk mental state' (ARMS) aim to prevent transition to first-episode psychosis (FEP), in addition, early intervention services for other mental health disorders have also been developed. The aim of the current study was to determine the proportion of young people attending a specialist FEP service who had been referred via other early intervention clinics, including an ARMS clinic, and compare the characteristics to those who presented directly to the FEP service. METHODS: We included young people diagnosed with FEP who received treatment at Orygen between 01.01.2012 and 31.12.2016. We examined rates of direct entry to the First Episode Psychosis service and rates from other early intervention services, specifically ARMS, personality disorders, mood disorders and a primary care youth mental health service clinics. RESULTS: 1138 young people were diagnosed with a FEP, of whom 13.7% first attended an ARMS clinic and a further 7.6% attended other youth mental health services. Individuals who first presented to an ARMS clinic were more likely to be female, younger, and less likely to be migrants or use substances. Rates of both voluntary and involuntary hospital admissions were significantly reduced for young people who transitioned from the ARMS clinic, the personality disorder clinic or the primary care service compared to those who presented directly with FEP. CONCLUSIONS: A significant proportion of young people with FEP initially attended another specialist youth mental health service, and importantly, they had much lower rates of hospital admission at the time of transition to FEP.

Heart development in two populations of Atlantic killifish (Fundulus heteroclitus) following exposure to a polycyclic aromatic hydrocarbon mixture.

Historic industrial pollution of the Elizabeth River, Virginia resulted in polycyclic aromatic hydrocarbon (PAH) contamination in sediments. Atlantic killifish (Fundulus heteroclitus) inhabiting the Atlantic Wood (AW) industrial site adapted to complex PAH mixture at this Superfund site. Their embryos have proved highly resistant to cardiac abnormalities indicative of PAH toxicity. In this study, embryos spawned from adults collected at AW and King's Creek (KC), a reference site, were exposed at 24 h post fertilization (hpf) to Elizabeth River Sediment Extract (ERSE), a complex PAH mixture, in a range of concentrations (0, 5.04, 50.45, 100.90, 151.35, or 252.25 µg/L total PAHs). Embryos were processed for histology at 144 hpf to enable evaluations of hearts at tissue and cellular levels. Morphometry and severity scoring were used to evaluate the extent of alterations. Unexposed embryos were similar in both populations. ERSE exposure resulted in multiple changes to hearts of KC embryos but not AW. Alterations were particularly evident in KC embryos exposed to concentrations above 1% ERSE (50.45 µg/L), which had thinner ventricular walls and larger pericardial edema. Individuals with moderate pericardial edema maintained arrangement and proximity of heart chambers, but changes were seen in ventricular myocytes. Severe pericardial edema was prevalent in exposed KC embryos and typically resulted in tube heart formation. Ventricles of tube hearts had very thin walls composed of small, basophilic cells and lacked trabeculae. Edematous pericardial fluid contained small amounts of proteinaceous material, as did controls, and was free of cells. This fluid was primarily unstained, suggesting water influx due to increased permeability. The use of histological approaches provided more specific detail for tissue and cellular effects in hearts of embryos exposed to PAHs and enabled understanding of potential links to later life effects of early life exposure.

Molecular Pathology Economics 101: An Overview of Molecular Diagnostics Coding, Coverage, and Reimbursement: A Report of the Association for Molecular Pathology.

Widespread indications for use of molecular diagnostics in various aspects of clinical medicine have driven proliferation of testing. The rapid adoption and continuous technological evolution of molecular diagnostics have often strained the development and maintenance of a functional underlying framework of coding, coverage, and reimbursement policies, thereby presenting challenges to various stakeholders, including molecular professionals, payers, and patients. A multidisciplinary working group convened by the Association for Molecular Pathology Economic Affairs Committee was tasked to describe the complex landscape of molecular pathology economics and highlight opportunities for member engagement. In this article, on the basis of review and synthesis of government regulations and procedures, published payer policy documents, peer-reviewed literature, and expert consensus, the Working Group navigates the ecosystem of molecular pathology economics in terms of stakeholders, coding systems and processes, coverage policy determination, and pricing mechanisms. The composition and interrelatedness of various working groups and committees are emphasized to highlight the functional underpinnings of the system. Molecular professionals must be conversant in the language and complex inner workings of molecular pathology economics to lead successful, viable laboratories and advocate effectively for policy development on their behalf. This overview is provided to be a resource to molecular professionals as they navigate the reimbursement landscape.

Altruistic Lying in an Alibi Corroboration Context: The Effects of Liking, Compliance, and Relationship between Suspects and Witnesses.

Police investigators, judges, and jurors are often very skeptical of alibi witness testimony. To investigate when and why individuals lie for one another, we conducted two studies in which witnesses' support of a false alibi was observed. We varied the level of social pressure exerted on witnesses and the level of affinity between suspect-witness pairs. During a study session purportedly intended to investigate dyadic problem-solving ability, a mock theft was staged. When questioned, participants were provided the opportunity to either corroborate or refute a confederate's false alibi that the latter was with them when the theft occurred. Participants were more likely to lie for the confederate when the latter explicitly asked participants to conceal his/her whereabouts during the time of the theft (Study 1). How much participants liked the suspect did not impact lying; however, participants lied for a confederate more often when the latter was a friend rather than a stranger (Study 2). Results show that alibi witnesses often lie and that investigators and jurors may not accurately estimate the likelihood that such witnesses will lie for one another. Witnesses who lied also reported doing so more often because they believed that the suspect was innocent rather than guilty. Copyright © 2016 John Wiley & Sons, Ltd.

Genomic Sequencing Procedure Microcosting Analysis and Health Economic Cost-Impact Analysis: A Report of the Association for Molecular Pathology.

The increasing use of advanced nucleic acid sequencing technologies for clinical diagnostics and therapeutics has made vital understanding the costs of performing these procedures and their value to patients, providers, and payers. The Association for Molecular Pathology invested in a cost and value analysis of specific genomic sequencing procedures (GSPs) newly coded by the American Medical Association Current Procedural Terminology Editorial Panel. Cost data and work effort, including the development and use of data analysis pipelines, were gathered from representative laboratories currently performing these GSPs. Results were aggregated to generate representative cost ranges given the complexity and variability of performing the tests. Cost-impact models for three clinical scenarios were generated with assistance from key opinion leaders: impact of using a targeted gene panel in optimizing care for patients with advanced non-small-cell lung cancer, use of a targeted gene panel in the diagnosis and management of patients with sensorineural hearing loss, and exome sequencing in the diagnosis and management of children with neurodevelopmental disorders of unknown genetic etiology. Each model demonstrated value by either reducing health care costs or identifying appropriate care pathways. The templates generated will aid laboratories in assessing their individual costs, considering the value structure in their own patient populations, and contributing their data to the ongoing dialogue regarding the impact of GSPs on improving patient care.

Lost proof of innocence: The impact of confessions on alibi witnesses.

The present study investigated how alibi witnesses react in the face of an innocent suspect's confession. Under the pretext of a problem-solving study, a participant and confederate completed a series of tasks in the same testing room. The confederate was subsequently accused of stealing money from an adjacent office during the study session. After initially corroborating the innocent confederate's alibi that she never left the testing room, only 45% of participants maintained their support of that alibi once informed that the confederate had confessed (vs. 95% when participants believed the confederate had denied involvement). Even fewer (20%) maintained their corroboration when the experimenter insinuated that their support of the alibi might imply their complicity. The presence of a confession also decreased participants' confidence in the accuracy of the alibi and their belief in the confederate's innocence. These findings suggest that a police-induced confession can strip an innocent confessor of a vital source of exculpatory evidence. This effect may well explain the often-puzzling absence of exculpatory evidence in many cases involving wrongful conviction.

Novel nucleosomal particles containing core histones and linker DNA but no histone H1.

Eukaryotic chromosomal DNA is assembled into regularly spaced nucleosomes, which play a central role in gene regulation by determining accessibility of control regions. The nucleosome contains ∼147 bp of DNA wrapped ∼1.7 times around a central core histone octamer. The linker histone, H1, binds both to the nucleosome, sealing the DNA coils, and to the linker DNA between nucleosomes, directing chromatin folding. Micrococcal nuclease (MNase) digests the linker to yield the chromatosome, containing H1 and ∼160 bp, and then converts it to a core particle, containing ∼147 bp and no H1. Sequencing of nucleosomal DNA obtained after MNase digestion (MNase-seq) generates genome-wide nucleosome maps that are important for understanding gene regulation. We present an improved MNase-seq method involving simultaneous digestion with exonuclease III, which removes linker DNA. Remarkably, we discovered two novel intermediate particles containing 154 or 161 bp, corresponding to 7 bp protruding from one or both sides of the nucleosome core. These particles are detected in yeast lacking H1 and in H1-depleted mouse chromatin. They can be reconstituted in vitro using purified core histones and DNA. We propose that these 'proto-chromatosomes' are fundamental chromatin subunits, which include the H1 binding site and influence nucleosome spacing independently of H1.

Direct inhibition of Gcn5 protein catalytic activity by polyglutamine-expanded ataxin-7.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion within the N-terminal region of the ataxin-7 protein, a known subunit of the SAGA complex. Although the mechanisms of SCA7 pathogenesis remain poorly understood, previous studies have shown perturbations in SAGA histone acetyltransferase function and transcriptional alterations. We sought to determine whether and how polyQ-expanded ataxin-7 affects SAGA catalytic activity. Here, we determined that polyQ-expanded ataxin-7 directly bound the Gcn5 catalytic core of SAGA while in association with its regulatory proteins, Ada2 and Ada3. This caused a significant decrease in Gcn5 histone acetyltransferase activity in vitro and in vivo at two SAGA-regulated galactose genes, GAL1 and GAL7. However, Gcn5 occupancy at the GAL1 and GAL7 promoters was increased in these cells, revealing a dominant-negative phenotype of the polyQ-expanded ataxin-7-incorporated, catalytically inactive SAGA. These findings suggest a dominant mechanism of polyQ-mediated SAGA inhibition that potentially contributes to SCA7 disease pathogenesis.

False alibi corroboration: witnesses lie for suspects who seem innocent, whether they like them or not.

To test the commonly held assumption that individuals who share a personal relationship are more likely to lie for one another than are strangers, 81 undergraduate students were given the opportunity to either corroborate or refute a confederate's alibi. In either a "friendship-enhancing" or a "stranger-maintaining" condition, confederate-participant pairs completed tasks under the pretext of a problem-solving study. During the experimental session, the confederate briefly left the testing room; upon her return she either came back empty handed (evidence absent) or with money in her hands (evidence present). Later, both the confederate and participant were questioned about a purported theft in an adjacent room. When questioned by the experimenter in the presence of the participant, the confederate provided a false alibi that she was in the testing room with the participant the entire time. The experimenter later questioned the participant alone and asked whether the confederate's statement was in fact true. Although we hypothesized that participants in the friendship-enhancing condition would corroborate the false alibi more often than those in the stranger-maintaining condition, participants in both conditions were as likely to support the alibi. In the "evidence-present" condition, however, participants were much less likely to corroborate the false alibi than in the "evidence-absent" condition. The results call into question our belief that closeness and affinity toward a suspect is important in judging the truthfulness of witness statements and emphasize the need for further empirical research on alibi corroboration. The research described also introduces a new and effective paradigm to directly measure false alibi corroboration.

Sgf29 binds histone H3K4me2/3 and is required for SAGA complex recruitment and histone H3 acetylation.

The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an important chromatin modifying complex that can both acetylate and deubiquitinate histones. Sgf29 is a novel component of the SAGA complex. Here, we report the crystal structures of the tandem Tudor domains of Saccharomyces cerevisiae and human Sgf29 and their complexes with H3K4me2 and H3K4me3 peptides, respectively, and show that Sgf29 selectively binds H3K4me2/3 marks. Our crystal structures reveal that Sgf29 harbours unique tandem Tudor domains in its C-terminus. The tandem Tudor domains in Sgf29 tightly pack against each other face-to-face with each Tudor domain harbouring a negatively charged pocket accommodating the first residue alanine and methylated K4 residue of histone H3, respectively. The H3A1 and K4me3 binding pockets and the limited binding cleft length between these two binding pockets are the structural determinants in conferring the ability of Sgf29 to selectively recognize H3K4me2/3. Our in vitro and in vivo functional assays show that Sgf29 recognizes methylated H3K4 to recruit the SAGA complex to its targets sites and mediates histone H3 acetylation, underscoring the importance of Sgf29 in gene regulation.

Differentiation of whole bacterial cells based on high-throughput microarray chip printing and infrared microspectroscopic readout.

Using robotic automation, a microarray printing protocol for whole bacterial cells was developed for subsequent label-free and nondestructive infrared microspectroscopic detection. Using this contact microspotting system, 24 microorganisms were printed on zinc selenide slides; these were 6 species of Listeria, 10 species of Vibrio, 2 strains of Photobacterium damselae, Yersinia enterocolitica 289, Bacillus cereus ATCC 14529, Staphylococcus aureus, ATCC 19075 (serotype 104 B), Shigella sonnei 20143, Klebsiella pneumoniae KP73, Enterobacter cloacae, Citrobacter freundii 200, and Escherichia coli. Microarrays consisting of separate spots of bacterial deposits gave consistent and reproducible infrared spectra, which were differentiated by unsupervised pattern recognition algorithms. Two multivariate analysis algorithms, principal component analysis and hierarchical cluster analysis, successfully separated most, but not all, the bacteria investigated down to the species level.

Effects of S-nitrosation on hemoglobin-induced microvascular damage.

Blood substitutes, such as diaspirin cross-linked hemoglobin (Hb), cause microvascular leakiness to macromolecules. Because of the potentially stabilizing effects of nitric acid (NO) on endothelium, experiments were performed to determine whether S-nitrosohemoglobin (SNO-Hb), a potential NO-donor Hb-based blood substitute, would not cause microvascular damage. Release of NO, or its metabolites, from the SNO-Hb was facilitated by addition of glutathione, which aids in the decomposition of S-nitrosothiols. In anesthetized rats, the mesenteric microvasculature was perfused with SNO-Hb with glutathione (six rats), SNO-Hb alone (six rats), or saline (eight rats) for 10 min, followed by fluorescein isothiocyanate (FITC)-albumin for 1 min, and finally fixed for epifluorescence microscopic examination. When comparing the SNO-Hb group with saline, both the numbers and areas of leaks were significantly increased [0.019 +/- 0.003 (SEM) microm vs. 0.0030 +/- 0.0004 and 7.36 +/- 1.50 vs. 0.156 +/- 0.035 (p < 0.005)]. With the addition of glutathione, leakage was still high (0.005 +/- 0.00005 microm and 5.086 +/- 0.064 microm) but decreased compared with SNO-Hb alone (p < 0.005). In conclusion, NO, or a related vasodilator, when released from SNO-Hb, significantly reduces but does not eliminate microvascular damage. Further improvements may result by S-nitrosating a more stable form of modified hemoglobin.

Neurotrophin receptor interacting factor (NRIF) is an essential mediator of apoptotic signaling by the p75 neurotrophin receptor.

Activation of the p75 neurotrophin receptor leads to a variety of effects within the nervous system, including neuronal apoptosis. Both c-Jun N-terminal kinase (JNK) and the tumor suppressor p53 have been reported to be critical for this receptor to induce cell death; however, the mechanisms by which p75 activates these pathways is undetermined. Here we report that the neurotrophin receptor interacting factor (NRIF) is necessary for p75-dependent JNK activation and apoptosis. Upon nerve growth factor withdrawal, nrif-/- sympathetic neurons underwent apoptosis, whereas p75-mediated death was completely abrogated. The lack of cell death correlated with a lack of JNK activation in the nrif-/- neurons, suggesting that NRIF is a selective mediator for p75-dependent JNK activation and apoptosis. Moreover, we document that NRIF expression is sufficient to induce cell death through a mechanism that requires p53. Taken together, these results establish NRIF as an essential component of the p75 apoptotic pathway.

A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF.

Neurotrophin signaling through the p75 receptor regulates apoptosis within the nervous system both during development and in response to injury. Whereas a number of p75 interacting factors have been identified, how these upstream factors function in a coordinated manner to mediate receptor signaling is still unclear. Here, we report a functional interaction between TRAF6 and the neurotrophin receptor interacting factor (NRIF), two proteins known to associate with the intracellular domain of the p75 neurotrophin receptor. The association between NRIF and TRAF6 was direct and occurred with both endogenous and ectopically expressed proteins. A KRAB repressor domain of NRIF and the carboxyl-terminal, receptor-binding region of TRAF6 were required for the interaction. Co-expression of TRAF6 increased the levels of NRIF protein and induced its nuclear translocation. Reciprocally, NRIF enhanced TRAF6-mediated activation of the c-Jun NH2-terminal kinase (JNK) by 3-fold, while only modestly increasing the stimulation of NF-kappaB. The expression of both NRIF and TRAF6 was required for reconstituting p75 activation of JNK in HEK293 cells, whereas NRIF mutants lacking the TRAF6 interaction domain were unable to substitute for the full-length protein in facilitating activation of the kinase. These results suggest that NRIF and TRAF6 functionally interact to facilitate neurotrophin signaling through the p75 receptor.