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Background and Hypothesis Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC). Study Design A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks. Study Results NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26). Conclusions NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with “Australian and New Zealand Clinical Trials” on the 30 May, 2016 (Registration Number: ACTRN12615001273572).

Background Health literacy (HL) has been defined as the ability of individuals to access, understand, and utilise basic health information. HL is crucial to patient engagement in treatment through supporting patient autonomy, informed consent and collaborative care. In people with physical disorders, poor HL is associated with poor health outcomes, but less is known about HL in people with severe mental illness. This study aimed to assess HL and investigate the associations between education, cognitive function, general literacy, and HL in participants with schizophrenia attending community mental health clinics. Method Fifty-two outpatients with schizophrenia attending a public community mental health clinic in Adelaide, Australia completed the Test of Functional Health Literacy in Adults—Short Form (S-TOFHLA) along with tests of cognition, aural and reading literacy and numeracy including Digit Symbol Coding (DSC), verbal fluency, the Wechsler Adult Intelligence Scale (WAIS-IV), Woodcock-Johnson III (Part 4 and 9) and the Lipkus numeracy scale. Sixty-one percent of participants were male. Participants had a mean age of 41.2 (SD 9.9) years and a mean of 11.02 (SD 1.5) years of education. Results The majority of participants had very poor aural and verbal literacy and poorer literacy correlated with fewer years of education. On the S-TOFHLA, 81% of participants had adequate HL; 6% were marginal and 13% were inadequate. There was a positive correlation between education and HL, with those with more years of education scoring higher for HL. There was also a significant association between better HL and better working memory and attention. Conclusions Consistent with previous research in schizophrenia, our participants had reduced educational attainment, aural and reading literacy and cognitive function compared to population norms. However, HL was better than expected given that previous research has found that people with psychiatric disorders tend to have lower HL, compared to the general population. This may reflect effective case management of our participants whilst attending the community clinics and supports ongoing research and intervention regarding HL in people living with mental illness.

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

Objective: To assess the impact, in the Australian setting, of the COVID-19 lockdown on antipsychotic supplies for patients with schizophrenia following a prescription from a new medical consultation when compared to the same periods in the previous 4 years. A secondary objective was to assess the volume of all antipsychotic supplies, from new and repeat prescriptions, over these same periods. Methods: A retrospective pharmaceutical claims database study was undertaken, using the Department of Human Services Pharmaceutical Benefits Scheme 10% sample. The study population included all adult patients with three or more supplies of oral or long-acting injectable antipsychotics for the treatment of schizophrenia at any time between 1 June 2015 and 31 May 2020. The primary outcome compared volumes of dispensed antipsychotics from new prescriptions (which require a medical consultation) between 1 April and 31 May each year from 2016 to 2020. This was to analyse the period during which the Australian Government imposed a lockdown due to COVID-19 (April to May 2020) when compared the same periods in previous years. Results: There was a small (5.7%) reduction in the number of antipsychotics dispensed from new prescriptions requiring a consultation, from 15,244 to 14,372, between April and May 2019 and the same period in 2020, respectively. However, this reduction was not statistically significant ( p = 0.75) after adjusting for treatment class, age, gender, location and provider type. Conclusion: The COVID-19 restrictions during April and May 2020 had no significant impact on the volume of antipsychotics dispensed from new prescriptions for patients with schizophrenia when compared to the volume of antipsychotics dispensed from new prescriptions during the same period in previous years.

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.

Background: This paper discusses the process of co-design of a de-colonising participatory methodology that enabled an international PhD student to work respectfully with Aboriginal community members and Elders, health professionals and consumers, and non-Indigenous service providers in a drug and alcohol and mental health comorbidity project in Adelaide, South Australia. The Comorbidity Action in the North project sought to redesign services to better meet the needs of local people affected by drug, alcohol, and mental health comorbidity. This arm of the study focused on the needs of Indigenous peoples. Methods: The PhD student, Aboriginal Elder mentor, Aboriginal Working Party and supervisors (the research team) sought to co-design a methodology that could address the following challenges: many Aboriginal people deeply distrust Western research due to past poor practices and a lack of implementation of findings into practice; Aboriginal people often remain unheard, unacknowledged and unrecognised in research projects; drug and alcohol and mental health comorbidity experiences are often distressing for Aboriginal community members and their families; attempts to access comorbidity care often result in limited or no access; Aboriginal community members experience acts of racism and discrimination as health professionals and consumers of health and support services; and, the PhD student was an international student with no existing relationship with local Aboriginal community members. The research team considered deeply how knowledge is shared, interpreted, owned and controlled, by whom and how, within research, co-morbidity care and community settings. The PhD student was supported to co-design a methodology that was equitable, democratic, liberating and life-enhancing, with real potential to develop feasible solutions. Results: The resulting combined Participatory Action Research (PAR)-Dadirri-Ganma methodology sought to create a bridge across Western and Aboriginal knowledges, understanding and experiences. Combined mentoring by senior Elders, Indigenous methodologies Dadirri (deep listening) and Ganma (two-way knowledge sharing), and Western PAR.Conclusions: Concepts within this paper are shared from the perspective of the PhD student with the permission and support of local Elders and Working Group members. The intention is to share what was learned for the benefit other students, research projects and community members who are beginning a similar journey.

Individualized metacognitive training (MCT+) is a novel psychotherapy that has been designed to specifically target delusional beliefs in people with psychosis. It works by developing an awareness of the implausible content of delusional beliefs, while also targeting the cognitive biases that contribute to their formation and maintenance. It was expected that MCT+ would lead to significantly greater reductions in delusional severity compared to a cognitive remediation (CR) active control condition. A total of 54 patients with a schizophrenia spectrum disorder and active delusions were randomized into four 2-hourly sessions of MCT+ (n = 27) or CR (n = 27). All participants completed posttreatment assessment, and only 2 participants did not complete 6-month follow-up assessment, resulting in MCT+ (n = 26) and CR (n = 26) for final analysis. The primary outcome measures of delusional and positive symptom severity were assessed rater-blind; secondary outcome assessment was non-blinded and included clinical and cognitive insight, the jumping to conclusions (JTC) bias, and cognitive functioning. Participants in the MCT+ condition showed significant reductions in delusional and overall positive symptom severity (large effect) and improved clinical insight (moderate effect) relative to CR controls. In contrast, CR controls showed moderate improvement in problem-solving ability relative to MCT+, but no other cognitive domain. Importantly, these findings were maintained at 6-month follow-up. The study adds further efficacy to the MCT program, and suggests that even brief psychotherapy can help to ameliorate the symptoms of psychosis.

Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood–brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into “high inflammation” and “low inflammation” subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The “high inflammation” schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both “low inflammation” schizophrenia and “low inflammation” control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in “high inflammation” schizophrenia compared to both “low inflammation” schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of “high inflammation” schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.

Alcohol dependence is a worldwide problem with a great social and economic burden in many countries. A number of studies have suggested that BDNF (mature BDNF) and its precursor (proBDNF) play important roles in the alcohol dependence. However, what roles of the mBDNF/proBDNF pathways play during the pathological process of alcohol dependence are not clearly understood. In our clinical study, peripheral blood was sampled from 30 male patients with alcohol dependence and 50 healthy males (as control). The protein levels of proBDNF, p75NTR, sortilin, mBDNF, TrkB and mRNA levels of BDNF, p75NTR, sortilin, and TrkB were detected in the peripheral blood in our study. We found that the protein levels of proBDNF and p75NTR were increased, but not the sortilin protein level; while the TrkB protein level was decreased in the alcohol dependence patients compared with healthy controls. Moreover, the mRNA levels of p75NTR and sortilin from the lymphocytes were slightly increased; while BDNF and TrkB were significantly decreased. The ELISA results of mBDNF and TrkB were declined in the alcohol dependence group. The levels of mBDNF and TrkB were negatively correlated with the average amount of daily ethanol consumption, and the levels of proBDNF, p75NTR and sortilin were positively correlated with the average amount of ethanol consumption per day. The ratio of proBDNF to mBDNF was altered in alcohol dependence patients. The balance between the proBDNF/p75NTR and mBDNF/TrkB signalling pathways appeared dysregulated in alcohol dependence. Our results suggested that both pathways may participate in the complex processes of alcohol dependence.

Adam J Savitz,1 Haiyan Xu,2 Srihari Gopal,1 Isaac Nuamah,2 Paulien Ravenstijn,3 David Hough,1 Maju Mathews,4 Yu Feng,5 Lu Yu,6 Masayoshi Takahashi,7 Dennis Liu,8 Gang Wang,9 Jin-Sang Yoon,10 Jiahn-Jyh Chen11 1Department of Central Nervous System, 2Department of Clinical Biostatistics, Janssen Research & Development, LLC, Titusville, NJ, USA; 3Department of Clinical Pharmacology, Janssen Research & Development, Beerse, Belgium; 4Global Medical Affairs, Neurosciences, Janssen Research & Development, NY, USA; 5Medical Affairs, Neurosciences, Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore; 6Department of Clinical Development, Janssen Research & Development, Beijing, China; 7Department of Central Nervous System, Janssen Pharmaceutical KK, Tokyo, Japan; 8Playford Community Team, Northern Adelaide Local Health Network, Adelaide, SA, Australia; 9National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Affiliated Capital University of Medical Science, Beijing, China; 10Department of Psychiatry, Chonnam National University Hospital, Gwangju, South Korea; 11Department of Geriatric Psychiatry, Taoyuan Mental Hospital, Taoyuan, Taiwan Objective: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study. Patients and methods: Of 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50–150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan–Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety. Results: A total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P

Background People with psychotic disorders, including schizophrenia, suffer premature cardiovascular morbidity and mortality. Obesity is a major factor in cardiometabolic disorders in this population. There has been very little research investigating differences in patterns of obesity in diverse ethnic populations. Guidelines for treatment of complex comorbidities in people with schizophrenia and related psychoses may need to provide specific recomendations for different ethnic groups. Methods The Chinese sample consisted 192 subjects were recruited from the outpatients and inpatients department of the psychiatry department of the third affiliated hospital of Sun Yat-sen. All enrolled subjects were Chinese Han ethnicity, aged 16–45 years, with a diagnosis of schizophrenia according to ICD-10 criteria for schizophrenia, excluding other acute psychiatric disorders. The Australian sample (N=1825) were drawn from the Survey of High Impact Psychosis. BMI and central obesity were measured in all subjects. Results 10.3% of men and 4.7% of women in the China sample were obese (BMI>30). In the Australian sample, 41.6% of men and 50.3% of women were obese. Overall, 7.8% of Chinese sample and 45.1% of the Australian sample were obese. However, amongst the non-obese China sample, 41.7% of men and 53.1% of women had central obesity; the mean for all non-obese Chinese people was 46.7%. 73% of non-obese Australian men and 81.5% of non-obese Australian women had central obesity; the mean for all non-obese Australians was 76%. Discussion Chinese Han people with schizophrenia have much lower rates of obesity than the Australian sample. In both groups, rates of abdominal obesity were higher than rates of obesity as defined by BMI. These ethnic differences may help in understanding the high rates of cardiometabolic disorder in people with psychotic disorders in Western countries. They may also inform interventions to assist Western people with psychoses to maintain better physical health.

Background Higher inflammation has been identified in a substantial subset of both high-risk and chronically ill patients with schizophrenia and related psychoses and this may account for some of the heterogeneity of the schizophrenia. There is also much heterogeneity in cognitive deficits related to schizophrenia with some patients showing a marked decline from premorbid intellectual levels while others show little change from either normal or low intellect. However, the relationship between intellectual change with the illness onset and inflammation in schizophrenia has not been established. Methods Here, we report the assessment of two common markers of inflammation from two independent samples of generally chronically ill patients with schizophrenia and related psychoses (one sample of 73 patients versus 70 healthy controls from Sydney, NSW, Australia and one sample of 297 patients from Syracuse, NY, USA). Peripheral venous blood samples were collected from all patients and blood markers of inflammation (C-Reactive Protein, CRP, and Neutrophil to Lymphocyte Ratio, NLR) were assayed using standard procedures. Assessment of premorbid and current intellectual abilities were obtained from the Sydney cohort of patients. Results Grouping the patients and controls from the Sydney sample into those with elevated (> 3 mg/L) versus normal (< 3 mg/L) CRP levels revealed 42% of the patients versus 20% of the healthy controls had elevated CRP (Chi Square = 9.16, p = .002) and further evidence of inflammation with an elevated mean NLR of 2.5. The frequency of peripheral inflammation was confirmed by the independent sample from Syracuse in which 39% of the patients (n= 115) had an elevated NLR above a cutoff score for normal of 2.2 which was consistent with the Sydney sample. Patients from the Sydney sample who had an elevated CRP also had a significant mean 15-point IQ decline from premorbid IQ levels, whereas the patients with CRP levels within normal limits did not show a statistically significant drop in IQ from premorbid levels (mean IQ decline 7.6 points). Healthy controls with normal CRP had no IQ change (0.0 points) and healthy controls with elevated CRP has a slight, non-significant IQ decline (mean 2.3 points). Discussion Thus, our study showed supportive evidence of elevated peripheral inflammation markers in subgroups of chronically ill patients with schizophrenia from two independent samples and a link between marked intellectual decline from premorbid levels and current peripheral inflammation in one chronically ill subgroup of patients with schizophrenia suggesting a role for inflammation in the cognitive impairment of a substantial proportion (40%) of patients with schizophrenia.

Estimating seasonal influenza prevalence is of undeniable public health importance, but remains challenging with traditional datasets due to cost and timeliness. Digital epidemiology has the potential to address this challenge, but can introduce sampling biases that are distinct to traditional systems. In online participatory health surveillance systems, the voluntary nature of the data generating process must be considered to address potential biases in estimates. Here we examine user behaviours in one such platform, FluTracking, from 2011 to 2017. We build a Bayesian model to estimate probabilities of an individual reporting in each week, given their past reporting behaviour, and to infer the weekly prevalence of influenza-like-illness (ILI) in Australia. We show that a model that corrects for user behaviour can substantially effect ILI estimates. The model examined here elucidates several factors, such as the status of having ILI and consistency of prior reporting, that are strongly associated with the likelihood of participating in online health surveillance systems. This framework could be applied to other digital participatory health systems where participation is inconsistent and sampling bias may be of concern.

BACKGROUND: Schizophrenia is characterized by positive and negative symptoms and cognitive deficits related to functional disability. Approved treatments targeting small molecule neurotransmitter receptors are limited in their effectiveness and often leave residual symptoms and debilitating side effects. Psychotic symptoms, cognitive deficits, and treatment response are variable in schizophrenia, highlighting heterogeneity in the etiology and presentation of the illness. There is a critical need for novel treatments targeting subgroups related to underlying biology that can be identified by biomarkers. A substantial subgroup (40%) of people with schizophrenia can be distinguished by cytokines in both peripheral blood and in brain. The cytokine interleukin 1-beta (IL-1β) mRNA and protein levels are significantly increased in serum, plasma, white blood cells, cerebrospinal fluid and brain in chronically ill patients and in first episode psychosis. Canakinumab is an approved human anti-IL-1β monoclonal antibody that interferes with the bioactivity of IL-1β and interrupts excessive immune response. However, the extent to which IL-1β blockade by canakinumab can reduce peripheral markers of an overactive immune system (e.g., high sensitivity C-reactive protein: hsCRP) and reduce psychotic symptom severity in schizophrenia is unknown. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel group trial of the monoclonal antibody canakinumab to block IL-1β in schizophrenia. Twenty-seven chronically ill patients with schizophrenia or schizoaffective disorder who had elevated peripheral inflammation markers (IL-1β, IL-6, hsCRP and/or neutrophil to lymphocyte ratio) at baseline were randomized to a one-time subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive treatment to antipsychotics. Peripheral hsCRP levels were measured at baseline (prior to injection) and at 1, 4- and 8-weeks post treatment. Positive and Negative Syndrome Scale scores were assessed at baseline and at 4- and 8-weeks post treatment. RESULTS: Separate t-tests comparing canakinumab or placebo at weeks 1, 4, and 8 to baseline showed significant reductions in peripheral hsCRP levels at all time points (all p’s < .02) for canakinumab only. Separate t-tests also showed a significant reduction in positive symptom severity scores at week 8 (p = 0.05) for canakinumab and at week 4 (p = 0.02) for placebo. There was a trend for low peripheral hsCRP levels to be strongly correlated with low positive symptom severity scores (r = .57, p = .07) only at week 8 in the canakinumab group. There were no significant reductions in negative or general psychopathology symptom severity scores in either group. DISCUSSION: Blockade of the cytokine IL-1β by the monoclonal antibody canakinumab significantly reduces peripheral hsCRP serum levels and these reductions may be related to a reduction in positive symptom severity in chronically ill patients with schizophrenia. Importantly, only those patients who initially displayed elevated peripheral markers of inflammation were recruited. The effects of canakinumab on the reduction of peripheral hsCRP is potentially beneficial to general health. The relatively strong relationship between the effects of canakinumab on the biological marker hsCRP and positive symptom severity after 8 weeks of treatment supports the effect of canakinumab on positive symptom severity. Given that treatment with a monoclonal antibody is a novel and substantial advance in the potential treatment of psychotic symptom severity in schizophrenia, future studies should consider increased or top-up doses with longer follow-up to confirm the benefit of adjunctive canakinumab treatment in schizophrenia.

Background This study examined the prevalence of risk factors for cardiovascular (CV)-related morbidity and mortality in young people with psychosis aged 18 to 24 years. Methods The study included 132 people aged 18 to 24 years who participated in the 2010 second Australian national survey of people living with psychosis. The 2009 World Health Organisation (WHO) Global Health Risks report was used as a framework to determine which specific risk factors were present in each in these young people. The risk factors assessed in this study were smoking, alcohol use, hypertension, overweight/obesity, physical inactivity, high blood glucose, high cholesterol and poor diet. Each risk factor was defined according to WHO criteria. A count of the total number of risk factors present for each participant was determined. Data for male and female participants were compared. Results Young men had an average of 2.9 (SD 1.2) risk factors. Young women had an average of 2.4 (SD 1.2) risk factors. The most common risk factors were low fruit and vegetable intake (77.9%), cigarette smoking (67.7%), overweight/obesity (55%) and physical inactivity (39.8%). There were no significant differences between men and women in the number of risk factors present, or the prevalence of individual risk factors. Conclusion This study demonstrated that many of the risk factors that ultimately contribute to disability and premature death are present at an early age in people with psychosis. Preventive measures need to be an integral component of early intervention services for this client population to avert progression to serious CV morbidity and early mortality.

BACKGROUND Web-based information and interventions for mental illness are increasingly being provided. There is an expectation that citizens have access to the internet and are competent in using technology. People with schizophrenia are often excluded from social engagement, have cognitive impairment, and have very limited income, all of which may reduce their use of technology. OBJECTIVE This study aimed to investigate technology access, use of digital technology, and confidence in using technology among people with schizophrenia living in the community. METHODS Face-to-face structured interviews with 50 people with schizophrenia (aged 18-65 years) living in the northern suburbs of Adelaide, South Australia, were conducted using an instrument designed to assess technology access and utilization. RESULTS Most participants (42/50, 84%) owned a mobile phone, but only 58% (29/50) owned a smartphone. Two-thirds of participants (33/50, 66%) had access to the internet at home, using a smartphone or computer. Moreover, 40% (20/50) of participants used the internet at least daily, but 30% (15/50) of participants had never accessed the internet from any device. Approximately half of the participants (24/50, 48%) had never used Facebook. Participants rarely used community facilities (eg, libraries and cafes) to access the internet. There were no significant differences (P values ranged from .14 to .70) between younger participants (aged 18-34 years) and older participants (aged 35-64 years) in internet or smartphone access or confidence in using technology. CONCLUSIONS Although the sample size of this study is small, it shows limited technology access, use of digital technology, and confidence in using technology among the participants. This could be a barrier to the online delivery of information and interventions for people with schizophrenia. To better understand the impacts of such technological disadvantage and potential disparities in access and use of online resources, prospective studies should recruit a larger sample size and include control subjects matched for socioeconomic disadvantage.

Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Background Web-based information and interventions for mental illness are increasingly being provided. There is an expectation that citizens have access to the internet and are competent in using technology. People with schizophrenia are often excluded from social engagement, have cognitive impairment, and have very limited income, all of which may reduce their use of technology. Objective This study aimed to investigate technology access, use of digital technology, and confidence in using technology among people with schizophrenia living in the community. Methods Face-to-face structured interviews with 50 people with schizophrenia (aged 18-65 years) living in the northern suburbs of Adelaide, South Australia, were conducted using an instrument designed to assess technology access and utilization. Results Most participants (42/50, 84%) owned a mobile phone, but only 58% (29/50) owned a smartphone. Two-thirds of participants (33/50, 66%) had access to the internet at home, using a smartphone or computer. Moreover, 40% (20/50) of participants used the internet at least daily, but 30% (15/50) of participants had never accessed the internet from any device. Approximately half of the participants (24/50, 48%) had never used Facebook. Participants rarely used community facilities (eg, libraries and cafes) to access the internet. There were no significant differences (P values ranged from .14 to .70) between younger participants (aged 18-34 years) and older participants (aged 35-64 years) in internet or smartphone access or confidence in using technology. Conclusions Although the sample size of this study is small, it shows limited technology access, use of digital technology, and confidence in using technology among the participants. This could be a barrier to the online delivery of information and interventions for people with schizophrenia. To better understand the impacts of such technological disadvantage and potential disparities in access and use of online resources, prospective studies should recruit a larger sample size and include control subjects matched for socioeconomic disadvantage.

Background Schizophrenia is a disabling and often unremitting mental illness with an unknown cause that is characterized by heterogeneity in psychotic symptom presentation, cognitive deficits and treatment response. There is accumulating evidence for the role of inflammation in the etiology of schizophrenia. Inflammatory markers have been identified in the brains and peripheral blood of chronically ill patients with schizophrenia and in first episode patients and these markers have been associated with structural and functional brain abnormalities and cognitive deficits. Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein expressed on endothelial cells which binds to leukocyte receptors that promotes transmigration of white blood cells into tissue. While peripheral inflammatory markers are altered in people with schizophrenia relative to controls, the extent to which ICAM-1 is elevated in the brains of people with schizophrenia and peripheral levels of soluble ICAM-1 (sICAM-1) is increased in relation to cognitive impairment in schizophrenia is unknown. Methods In a post-mortem cohort, 8 mRNAs relating to BBB function and 3 immune cell markers were measured by qPCR in the prefrontal cortex of 37 people with schizophrenia and 37 matched controls. In an independent living cohort, sICAM-1 was measured with a Luminex immunoassay from the plasma of 78 chronically ill patients with schizophrenia (all receiving antipsychotic medication) and 73 healthy controls. All participants from the living cohort received the following cognitive assessments: Wechsler Adult Intelligence Scale – 3rd edition to assess current IQ, Controlled Oral Word Association Test verbal fluency and Wechsler Memory Scale-Revised to assess verbal memory. Pearson’s or Spearman’s correlations were performed between cognitive measures and sICAM1 levels as appropriate in schizophrenia patients and healthy controls. Results ICAM-1 was elevated in the brains of people with schizophrenia relative to controls and CD163+ perivascular macrophages were found in the parenchyma. Peripheral sICAM1 was elevated by 29.2% in people with schizophrenia compared to healthy controls, t(140) = -3.988, p < 0.01. In people with schizophrenia, sICAM1 was inversely correlated with immediate verbal memory (r=-0.30, p=0.01), delayed verbal memory (rho=-0.29, p=0.01), verbal abstract reasoning (r=-0.23, p=0.05), and processing speed (rho=-0.28, p=0.02). In healthy controls, sICAM1 levels were inversely correlated with verbal fluency (r=-0.27, p=0.03) and processing speed (rho=-0.26, p=0.03). Discussion The brain endothelium of people with schizophrenia can attract more immune cells via increased ICAM-1. sICAM-1, a cleavage product of ICAM which enables white blood cell migration into tissue (including brain) is significantly elevated in peripheral blood of patients with schizophrenia. sICAM-1 is associated with poor verbal memory, reasoning and processing speed in people with schizophrenia and accounts for variation in cognition of healthy controls. This suggests that increased inflammatory processes, measured in blood, may reflect brain related cognitive deficits that are the hallmark of schizophrenia. Anti-inflammatory treatments may reverse cognitive impairment in schizophrenia.

Background Obstructive sleep apnoea (OSA) is characterised by repeated collapse of the upper airway during sleep, causing hypoxia, frequent arousals and disruption to sleep architecture. OSA is more likely in people who are obese, smoke tobacco, and use alcohol and sedating medications – all these factors are more common in schizophrenia. OSA is likely to be underdiagnosed in schizophrenia as symptoms such as non-restorative sleep, depression and daytime somnolence may be attributed to chronic mental illness. OSA in the normal population is associated with cognitive deficits and poor cardiovascular health, both of which are common in schizophrenia, so comorbid OSA in schizophrenia may be exacerbating these problems. Treatment of OSA with continuous positive airway pressure (CPAP) reduces daytime sleepiness, and improves quality of life, cognitive function, and cardiovascular risk factors. There are no published studies of CPAP treatment of OSA in schizophrenia, so it is not known whether these benefits also occur in the patient population. Methods Previous research into OSA in schizophrenia has utilised subjective screening instruments and there are no large studies using polysomnography (PSG), the gold standard method to diagnose OSA. We undertook home sleep studies using polysomnography in 30 people with schizophrenia, treated with clozapine. Participants cooperated well and all studies were of good quality. We treated 6 participants with severe OSA with CPAP. Treatment adherence was good with mean CPAP usage of of 7.7 hours/night. Results We found that 14/30 (40%) of our participants with schizophrenia had OSA and 8/30 (27%) had severe OSA; twice the prevalence of severe OSA in the general population. After six months CPAP treatment there was significant improvement in cognition, especially verbal memory, working memory and motor skills. Average weight loss was 7.2kg (SD 9k) with a 12mmHg (SD 18) reduction in systolic blood pressure. Normal sleep architecture was restored: on average the percentage of the night spent in restorative slow wave sleep increased from 4.8% to 31.6%, and the percentage in REM sleep from an average of 4.1% to 31.4%. The mean percentage of the night spent in a hypoxic state with oxygen saturation less than 90% reduced from an average of 27.6% to 2%. Discussion Improved awareness of the high prevalence of OSA in schizophrenia and access to diagnostic screening by home PSG should ensure this important comorbid condition is not missed. CPAP treatment for OSA in people with schizophrenia is feasible and has the potential to improve both cognition and cardiovascular health, resulting in better functioning and reduced cardiovascular morbidity.

Background: Cytokine messenger RNA (mRNA) transcripts derived from peripheral blood can be used to identify individuals with putative inflammation, and patients with schizophrenia increased proportions of those with elevated cytokines. However, the reliability of the TwoStep clustering algorithm, used to identify elevated cytokine subsets, has not been systematically examined. Here we use bootstrapping procedures to assess the reliability of this method.

Background: The kynurenine pathway (KP) of tryptophan (TRP) catabolism is considered to link the immune and neurotransmitter systems. The KP metabolite kynurenic acid (KYNA) shows increases in the brain of patients with schizophrenia. Here, we tested whether changes in brain KP enzyme mRNAs and plasma KP metabolites are related to cytokine levels in schizophrenia. We expected Kynurenine Aminotransferase II (KATII) mRNA to be increased in brains of people with schizophrenia, particularly in patients displaying elevated cytokines. Furthermore, we expected that the kynurenine (KYN)–TRP ratio in the plasma of chronically ill patients to be associated with cognitive and brain volume abnormalities in schizophrenia with high inflammation.

Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40–60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered ‘clozapine resistant’. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ. This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes. This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a ‘go to’ adjunct in patients that are only partly responsive to clozapine. Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.

Chronic exposure to stressful environment is a key risk factor contributing to the development of depression. However, the mechanisms involved in this process are still unclear. Brain-derived neurotropic factor (BDNF) has long been investigated for its positive role in regulation of mood, although the role of its precursor, proBDNF, in regulation of mood is not known. In this study, using an unpredictable chronic mild stress (UCMS) paradigm we found that the protein levels of proBDNF were increased in the neocortex and hippocampus of stressed mice and this UCMS-induced upregulation of proBDNF was abolished by chronic administration of fluoxetine. We then established a rat model of UCMS and found that the expression of proBDNF/p75NTR/sortilin was upregulated, whereas the expression of mature BDNF and TrkB was downregulated in both neocortex and hippocampus of chronically stressed rats. Finally, we found that the injection of anti-proBDNF antibody via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) approaches into the UCMS rats significantly reversed the stress-induced depression-like behavior and restored the exploratory activity and spine growth. Although intramuscular injection of AAV-proBDNF did not exacerbate the UCMS-elicited rat mood-related behavioral or pathological abnormalities, i.c.v. injection of AAV-proBDNF increased the depression-like behavior in naive rats. Our findings suggest that proBDNF plays a role in the development of chronic stress-induced mood disturbances in rodents. Central (i.c.v.) or peripheral (i.p.) inhibition of proBDNF by injecting specific anti-proBDNF antibodies may provide a novel therapeutic approach for the treatment of stress-related mood disorders. Refereed/Peer-reviewed

Biology teachers are accustomed to engaging individuals who do not accept biological evolution. Denial of evolution ranges from ignorance of the evidence to outright denial or distortion of data. The list of science denial topics has grown alarmingly over the years to include: HIV as the cause of AIDS, exaggeration of the health and environmental risks of genetically modified organisms, existence of holes in the ozone layer, the rise in antibiotic resistance, health risks caused by cigarette smoking, exaggeration and denial of harmful side effects of pesticides, water and environmental damage caused by hydraulic fracturing, the fear that vaccines do more harm than good, and, of course, global warming and climate change. Teaching climate science has become so perilous in some school districts that the National Center for Science Education, long known for activism in the arena of evolution education, has greatly expanded efforts in the arena of climate (http://ncse.com/climate).

Background Health literacy (HL) has been defined as the degree to which individuals possess the capacity to obtain, process, understand and utilise basic health information. For people with schizophrenia, important aspects of their HL include the ability to understand information about their illness and treatment, taking medications correctly, and interacting with clinicians. Schizophrenia is associated with lower levels of education, which has been found to negatively impact on HL. Further, schizophrenia is often associated with cognitive impairment, but the relationship between HL and cognitive function in this patient population is not known. Studies of HL in people with physical disorders have demonstrated that people with poor HL have poorer outcomes, with greater morbidity and mortality. There has been very little research into HL in schizophrenia, although it may be expected that those with poor HL might have more difficulty managing their illness and interacting with clinical services. Methods People living in the community, and attending public community mental health outpatient clinics in the Northern suburbs of Adelaide, Australia, were invited to participate in the study. They were interviewed by trained research staff, and completed the WAIS VI digit symbol coding (DSC), Verbal Fluency (VF; animal naming), the short version of the Test of Functional Health Literacy in Adults (S-TOFHLA) along with two parts of the Woodcock-Johnson III measuring aural literacy (Part 4; WJ4) and reading literacy (Part 9; WJ9). Of 101 participants, 62 had schizophrenia, while the other 39 had a range of other diagnoses. Results The 62 participants with schizophrenia had a mean age of 41.2 (SD 9.9) years and 61% were male. They had a mean of 11.02 (SD 1.5) years of education. The remaining participants had a mean age of 43.3 (SD 13.4) years, 46% were male, and the mean years of education was 11.3 (SD 2.5). 90% of the schizophrenia group were at or below 8th grade (Year 8) level for aural literacy, and 63% were at or below 8th grade (Year 8) for reading literacy. Those with a schizophrenia diagnosis had lower scores on the WJ9 (mean 8.3, SD 4.5) compared with the non-schizophrenia group (mean 11, SD 5.1); t = 2:739; p = 0:007, medium Cohen’s D effect size (D = 0:548). However, there was not a significant difference (t = 1.975, p = .051) in aural literacy between the schizophrenia and non-schizophrenia groups. Using the S-TOFHLA, 81% of the schizophrenia group had adequate HL; 6% were marginal and 13% were inadequate. In contrast, 97% of the non-schizophrenia group had adequate HL. The schizophrenia group had lower mean S-TOFHLA scores (mean 28.6, SD 7.5; compared to mean 31.8, SD 4.8); t = 2.369; p = 0.020, medium Glass’s effect size (G = 0.657). In all subjects, there was a moderate, positive relationship (r = 0.359; p < .05) between education and the TOFHLA score. There was also a positive correlation between the S-TOFHLA score and the aural and reading literacy scores Discussion The majority of people with schizophrenia had very poor aural and verbal literacy, and there was a correlation between education and literacy skills, and HL. People with schizophrenia tend to have less years of school attendance, and cognitive impairment is a core component of the disorder. However, only 19% of the schizophrenia group had inadequate HL. This finding suggests that their HL skills are better than expected, given their educational and literacy deficits. This may reflect their engagement in case management and psychoeducation whilst attending the community MH clinic; the clinicians might have been providing effective ongoing education about managing their mental illness, medication and interactions with health services.

Background Information and interventions for mental illness are increasingly being provided on-line. There is an expectation that citizens have access to the internet and are competent in using technology. People with schizophrenia are often excluded from social engagement, have cognitive impairment and have very limited income; all of which may reduce their use of technology. This project aimed to assess the use of technology and the internet in people with schizophrenia or schizoaffective disorder, living in the community. Methods Face-to-face structured interviews were used to evaluate technology literacy, attitudes towards technology, and access and engagement with technology in 50 people with schizophrenia or schizoaffective disorder aged 18–65 years, living in the community. Results About half of the study population had access to a computer, and half had access to the internet at home. Participants’ most common uses of technology were voice-calling, messaging, surfing the internet and accessing Facebook. The use of more advanced functions of technology (calendar, banking, news, health information) were rare. The general attitude among participants was that technology was not a significant part of their lives. Discussion Technology literacy and internet access were limited in this population. This needs to be addressed before the on-line delivery of educational information, service information and e-health interventions can be widely utilised in people with schizophrenia.

Biology is well suited for mathematical description, from the perfect geometry of viruses, to equations that describe the flux of ions across cellular membranes, to computationally intensive models for protein folding. For this short Web review, however, I'm going to focus on how mathematics helps us as biologists sort, evaluate, and draw conclusions about our data. Just as computer technology has revolutionized lab work, computers have revolutionized data analysis, in particular with a host of graphically driven methods for sorting, evaluating, and comparing data. The highly technical, often automated, and computationally driven biology of today makes it important to keep students aware of the importance of understanding the underlying mathematics. Computers might seem magical to students, but they only perform the calculations humans tell them to do.

Molecular biology and advanced techniques informed by chemistry and physics have changed biological research and teaching. Today's students take for granted that as they study the life sciences, they will hear a lot about genes and molecules. Sir William Harvey would be profoundly disorientated and then gratified by a visit to the Harvey Society's website (www.harveysociety.org). The man who accurately described the functional anatomy of the circulatory system would appreciate the extent to which his evidence-based approach to animal physiology has won the day. Indeed, understanding life processes at a molecular level is immensely satisfying. Three cheers for reductionism (Figure 1). Figure 1. The i heart guts website sells plush toys based on most of your favorite internal organs. It can be difficult, however, to fully appreciate the beauty of molecular details if the larger functions they serve are poorly understood. After all, it is the anatomical genius of the circulatory system that ensures that every cell of the body benefits from the marvel of hemoglobin. The steadily growing body of biological information makes it more challenging to preserve places in the curriculum to provide organismal and physiological context for students, and to cultivate deep thinking about how complex biological systems function through emergent properties of molecular mechanics. We are all interested in how our bodies work and are obsessed, if not enthralled, by our innards, or as one website (http://iheartguts.com/) would put it, “we heart guts.” My main goal for this review is to uncover websites that can be used to infuse the biology curriculum with systems and organismal context. Because a human anatomy and physiology (A&P) sequence is still part of most life science curricula, websites that support the teaching of A&P vastly outnumber websites concerned with general physiological principles or comparative physiology and anatomy. I highlight websites that emphasize fundamental principles and a comparative approach, but I also point to several excellent sites devoted to human A&P (Figure 2). Figure 2. The University of Utah Medical Library has a number of outstanding educational resources and tutorials on its Knowledge Weavers website, including an excellent animation of the circulation through the heart. To honor Harvey, let's begin by looking at a website that does an outstanding job of showing how our hearts work. The Knowledge Weavers website (http://library.med.utah.edu/kw/) from the University of Utah medical library offers many excellent resources. Their Flash-animated heart (http://library.med.utah.edu/kw/resources.html#animations) is one of the best of many available on the Web. The action of the heart is linked to dynamic graphs of blood pressure/volume, electrocardiogram, and heart sounds. The progress of the heart cycle is tracked by systole and diastole, in turn subdivided into relevant phases, and controls are available to run the animation fast, slow, or in step-through mode. The Flash console conveniently locates links to tutorials. The tutorials, by dissecting the animation step by step, should help students consolidate their learning based on the animation. It would be an interesting assessment to have students make their own tutorials and then see how they measure up to those made by the website authors. In addition to the cardiology information, the site also has an interesting concept for presenting a functional neural pathway. The Osteointeractive section (http://library.med.utah.edu/kw/osteo/index2.html) is noteworthy in presenting topics such as forensic anthropology and paleopathology, including the use of bones for human rights work. They've also developed tools to help faculty make multimedia and Web-based quizzes.

What better time than the flu season to explore the realms of the viruses? From your nasal passages to the dirt under your feet, viruses are everywhere, in innumerable hordes. They display a dazzling array of geometries, from compact rods to voluminous dodecahedrons (12-sided polyhedron). While all viruses are small compared with our cells (∼10,000 nm in diameter), they range over many magnitudes, from the tiny poliovirus (30 nm in diameter) to the bacterial-sized poxvirus (450 nm in diameter). Viruses have evolved strategies for infecting all taxa, but most viruses are highly specific about their cellular host. In humans, viruses cause diverse diseases, from chronic but benign warts, to acute and deadly hemorrhagic fever. Viruses have entertaining names like Zucchini Yellow Mosaic, Semliki Forest, Coxsackie, and the original terminator, T4. But what I find most fascinating about viruses is their testimony to the power of information. To understand viruses, we need to explore and understand their structure, and we need to interrogate their genomes. In this article, I will review a number of websites that open a portal to the realms of the viruses. Figure 1. A colorized image of T4 bacteriophage at a cell's surface from Wikimedia (http://commons.wikimedia.org/wiki/Main_Page). The image accompanied an online article on the therapeutic potential of viruses (http://www.cosmosmagazine.com/node/1024) from Cosmos magazine.

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGFβ) superfamily of secreted molecules. BMPs play essential roles in multiple developmental and homeostatic processes in metazoans. Malfunction of the BMP pathway can cause a variety of diseases in humans, including cancer, skeletal disorders and cardiovascular diseases. Identification of factors that ensure proper spatiotemporal control of BMP signaling is critical for understanding how this pathway is regulated. We have used a unique and sensitive genetic screen to identify the plasma membrane-localized tetraspanin TSP-21 as a key new factor in the C. elegans BMP-like “Sma/Mab” signaling pathway that controls body size and postembryonic M lineage development. We showed that TSP-21 acts in the signal-receiving cells and genetically functions at the ligand-receptor level. We further showed that TSP-21 can associate with itself and with two additional tetraspanins, TSP-12 and TSP-14, which also promote Sma/Mab signaling. TSP-12 and TSP-14 can also associate with SMA-6, the type I receptor of the Sma/Mab pathway. Finally, we found that glycosphingolipids, major components of the tetraspanin-enriched microdomains, are required for Sma/Mab signaling. Our findings suggest that the tetraspanin-enriched membrane microdomains are important for proper BMP signaling. As tetraspanins have emerged as diagnostic and prognostic markers for tumor progression, and TSP-21, TSP-12 and TSP-14 are all conserved in humans, we speculate that abnormal BMP signaling due to altered expression or function of certain tetraspanins may be a contributing factor to cancer development., Author Summary The bone morphogenetic protein (BMP) signaling pathway is required for multiple developmental processes during metazoan development. Various diseases, including cancer, can result from mis-regulation of the BMP pathway. Thus, it is critical to identify factors that ensure proper regulation of BMP signaling. Using the nematode C. elegans, we have devised a highly specific and sensitive genetic screen to identify new modulators in the BMP pathway. Through this screen, we identified three conserved tetraspanin molecules as novel factors that function to promote BMP signaling in a living organism. We further showed that these three tetraspanins likely form a complex and function together with glycosphingolipids to promote BMP signaling. Recent studies have implicated several tetraspanins in cancer initiation, progression and metastasis in mammals. Our findings suggest that the involvement of tetraspanins in cancer may partially be due to their function in modulating the activity of BMP signaling.

The human brain contains an estimated 100 billion neurons, and browsing the Web, one might be led to believe that there's a Web site for every one of those cells. It's no surprise that there are lots of Web sites concerning the nervous system. After all, the human brain is toward the top of nearly everyone's list of favorite organs and of intrinsic interest to scientists and nonscientists alike. In this review I will focus primarily on three excellent Web sites that represent three very different approaches to Web design and educational media. At the end of this review, I list a number of noteworthy neuroscience Web sites but without extensive remarks.

Objectives The aim of the present study was to document Australian policies on the physical health of people with mental illness and evaluate the capacity of policy to support health needs. Methods A search of state and federal policies on mental and physical illness was conducted, as well as detailed analysis of policy content and the relationships between policies, by applying the World Health Organization Mental Health Action Plan 2013–2020 as an evaluative framework. Results National policy attention to the physical health of people with mental illness has grown, but there is little interconnection at the national and state levels. State policies across the country are inconsistent, and there is little evidence of consistent policy implementation. Conclusions A coherent national health policy framework on addressing co-occurring physical and mental illnesses that includes healthcare system reforms and ensuring the interconnectedness of other relevant services should be prioritised. What is known about the topic? People with mental illness have a lower life expectancy and poorer physical health than people who do not have a mental illness. Government policy is critical to reducing inequalities in physical health and increasing longevity. What does this paper add? Evaluating policy developments against the World Health Organization’s Mental Health Action Plan 2013–2020, this review identified a lack of cohesive national-level policy on how to improve the physical health of people with mental illness. Although there are some state-based policies regarding strategies for better prevention and management of the physical health of people with mental illness, evidence of policy implementation is either scarce or inconsistent. The capacity of current policy to translate into reforms that increase the physical and overall health of people suffering mental health difficulties seems very limited. What are the implications for practitioners? This paper outlines major policy gaps and an overall need for a national-level policy. National-level leadership on integrated health care is required, with monitoring to ensure health care reforms are genuinely informed by consumer and clinician views and are effective.