Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment.

Immune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. We used CMS subtyping on surgical resections from patients and aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, and tested the effects of their LPS on cytokine production of peripheral blood mononuclear cells (PBMCs). We focused on Fusobacterium periodonticum and Bacteroides fragilis in CMS1, and Porphyromonas asaccharolytica in CMS4. Treatment of PBMCs with LPS isolated from these bacteria showed that F. periodonticum stimulates cytokine production in PBMCs while both B. fragilis and P. asaccharolytica had an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties of F. periodonticum LPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.

The relationship between subjective sleep disturbance and attenuated psychotic symptoms after accounting for anxiety and depressive symptoms.

BACKGROUND AND HYPOTHESES: Sleep disturbances are increasingly recognized as cooccurring with psychotic symptoms. The potential importance of this relationship is complicated when considering the effects of anxiety and depressive symptoms which commonly present in early-stage illness states. This study aimed to investigate the relationship between self-reported sleep disturbance on the development of attenuated psychotic symptoms (APS) cross-sectionally and longitudinally while adjusting for roles of anxiety and depressive symptoms. DESIGN: Eight-hundred and two help-seeking young people aged 12 to 25 years who engaged with our Australian early intervention services were included in the study (the "Transitions" cohort). Cross sectional mediation and cross-lagged longitudinal (12-month) mediation models were developed with outcomes being different APS domains. RESULTS: Only baseline excessive daytime sleepiness predicted later APS when accounting for previous APS, anxiety and depressive symptomatology. Cross sectionally, self-reported sleep disturbance showed both direct and indirect predictive relationships with all APS domains. Partial mediation through anxiety and depression was shown for unusual thought content, perceptual abnormalities, and disorganised speech, while full mediation through depression was shown for non-bizarre ideas. CONCLUSIONS: The specificity of the relationship between self-reported sleep disturbance on APS highlights the potential for different roles in mechanistic models of psychotic symptom expression. This further indicates the need for further experimental research to illuminate potential causal pathways. Future research should continue to use continuous, symptom level approaches across a range of timeframes to more accurately model the complex dynamics present in the sleep-psychosis relationship.

Physical and mental health of older people while cocooning during the COVID-19 pandemic.

BACKGROUND: Cocooning or shielding, i.e. staying at home and reducing face-to-face interaction with other people, was an important part of the response to the COVID-19 pandemic for older people. However, concerns exist regarding the long-term adverse effects cocooning may have on their physical and mental health. AIM: To examine health trajectories and healthcare utilization while cocooning in a cohort of community-dwelling people aged ≥70 years. DESIGN: Survey of 150 patients (55% female, mean age 80 years and mean Clinical Frailty Scale Score 4.8) attending ambulatory medical services in a large urban university hospital. METHODS: The survey covered four broad themes: access to healthcare services, mental health, physical health and attitudes to COVID-19 restrictions. Survey data were presented descriptively. RESULTS: Almost 40% (59/150) reported that their mental health was 'worse' or 'much worse' while cocooning, while over 40% (63/150) reported a decline in their physical health. Almost 70% (104/150) reported exercising less frequently or not exercising at all. Over 57% (86/150) of participants reported loneliness with 1 in 8 (19/150) reporting that they were lonely 'very often'. Half of participants (75/150) reported a decline in their quality of life. Over 60% (91/150) agreed with government advice for those ≥70 years but over 40% (61/150) reported that they disliked the term 'cocooning'. CONCLUSIONS: Given the likelihood of further restrictions in coming months, clear policies and advice for older people around strategies to maintain social engagement, manage loneliness and continue physical activity and access timely medical care and rehabilitation services should be a priority.

Examining partnerships within an international knowledge translation network focused on youth mental health promotion.

BACKGROUND: Systems transformation for health promotion, involving engagement from multiple disciplines and levels of influence, requires an investment in partnership development. Integrated youth service is a collaborative model that brings organisations together to provide holistic care for youth. Frayme is an international knowledge translation network designed to support the uptake and scaling of integrated youth service. Social network analysis (SNA) is the study of relationships among social units and is useful to better understand how partners collaborate within a network to achieve major objectives. The purpose of this paper is to apply SNA to the Frayme network in order to (1) examine the level and strength of partnerships, (2) identify the strategies being employed to promote the main objectives and (3) apply the findings to current research in youth mental health and system transformation. METHODS: The PARTNER tool includes a validated survey and analysis software designed to examine partner interconnections. This tool was used to perform the SNA and 51 of the 75 partners completed the survey (14 researchers, 2 advisory groups and 35 organisations). A network map was created and descriptive frequencies were calculated. RESULTS: The overall network scores for the Frayme network were 20.6% for density, 81.5% for centralisation and 71.7% for overall trust. The Frayme secretariat received a 3.84 out of a possible 4 for value. In addition, the youth and family advisories each received a value score of 4 and all Leadership Team organisations received a score of 2.97 or above. CONCLUSIONS: The Frayme secretariat links many partners who would otherwise be disconnected and acts as a significant conduit for novel information. Frayme may have the opportunity to enhance value perceptions among broader network members by profiling individual organisations and the potential leveraging opportunities that might exist through their work. These findings increase understanding with respect to the mechanisms of network development and will be helpful to inform partnership development in the future. In addition, they contribute to the literature with respect to knowledge translation practice as well as the scaling of collaborative interventions within youth mental health.

The prognostic significance of attenuated psychotic symptoms in help-seeking youth.

BACKGROUND: Recent findings suggest that attenuated psychotic symptoms (APS) might serve as a risk factor for general mental health impairment in help-seeking youth. The current study was designed to test this possibility by examining the prognostic significance of APS in a large cohort of help-seeking youth not selected for psychosis risk. METHOD: 465 youth aged 12-25 referred to general youth mental health services were grouped as either APS + or APS- based on whether or not they met 'ultra high risk' for psychosis APS risk criteria as assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS). They completed clinical assessments at baseline and at 12-month follow-up, measuring a range of psychopathology (depression, anxiety, eating disorders, general psychological distress, substance abuse) and psychosocial functioning. RESULTS: APS + had significantly poorer outcomes at 12-months on a range of clinical variables, even after adjusting for baseline scores and amount of treatment received. However, the APS + group showed greater improvement in functioning at follow-up compared to APS-. CONCLUSION: Attenuated psychotic symptoms are a prognostic indicator of persistent transdiagnostic mental health problems and reduced response to treatment in help-seeking youth over the short term. Hence, it is critical to screen and assess attenuated psychotic symptoms at the primary and secondary mental health services level, especially given that these subclinical symptoms are rarely voluntarily reported.

Is testosterone linked to human aggression? A meta-analytic examination of the relationship between baseline, dynamic, and manipulated testosterone on human aggression.

Testosterone is often considered a critical regulator of aggressive behaviour. There is castration/replacement evidence that testosterone indeed drives aggression in some species, but causal evidence in humans is generally lacking and/or-for the few studies that have pharmacologically manipulated testosterone concentrations-inconsistent. More often researchers have examined differences in baseline testosterone concentrations between groups known to differ in aggressiveness (e.g., violent vs non-violent criminals) or within a given sample using a correlational approach. Nevertheless, testosterone is not static but instead fluctuates in response to cues of challenge in the environment, and these challenge-induced fluctuations may more strongly regulate situation-specific aggressive behaviour. Here, we quantitatively summarize literature from all three approaches (baseline, change, and manipulation), providing the most comprehensive meta-analysis of these testosterone-aggression associations/effects in humans to date. Baseline testosterone shared a weak but significant association with aggression (r = 0.054, 95% CIs [0.028, 0.080]), an effect that was stronger and significant in men (r = 0.071, 95% CIs [0.041, 0.101]), but not women (r = 0.002, 95% CIs [-0.041, 0.044]). Changes in T were positively correlated with aggression (r = 0.108, 95% CIs [0.041, 0.174]), an effect that was also stronger and significant in men (r = 0.162, 95% CIs [0.076, 0.246]), but not women (r = 0.010, 95% CIs [-0.090, 0.109]). The causal effects of testosterone on human aggression were weaker yet, and not statistically significant (r = 0.046, 95% CIs [-0.015, 0.108]). We discuss the multiple moderators identified here (e.g., offender status of samples, sex) and elsewhere that may explain these generally weak effects. We also offer suggestions regarding methodology and sample sizes to best capture these associations in future work.

Treating depression with physical activity in adolescents and young adults: a systematic review and meta-analysis of randomised controlled trials.

We aimed to establish the treatment effect of physical activity for depression in young people through meta-analysis. Four databases were searched to September 2016 for randomised controlled trials of physical activity interventions for adolescents and young adults, 12-25 years, experiencing a diagnosis or threshold symptoms of depression. Random-effects meta-analysis was used to estimate the standardised mean difference (SMD) between physical activity and control conditions. Subgroup analysis and meta-regression investigated potential treatment effect modifiers. Acceptability was estimated using dropout. Trials were assessed against risk of bias domains and overall quality of evidence was assessed using GRADE criteria. Seventeen trials were eligible and 16 provided data from 771 participants showing a large effect of physical activity on depression symptoms compared to controls (SMD = -0.82, 95% CI = -1.02 to -0.61, p < 0.05, I2 = 38%). The effect remained robust in trials with clinical samples (k = 5, SMD = -0.72, 95% CI = -1.15 to -0.30), and in trials using attention/activity placebo controls (k = 7, SMD = -0.82, 95% CI = -1.05 to -0.59). Dropout was 11% across physical activity arms and equivalent in controls (k = 12, RD = -0.01, 95% CI = -0.04 to 0.03, p = 0.70). However, the quality of RCT-level evidence contributing to the primary analysis was downgraded two levels to LOW (trial-level risk of bias, suspected publication bias), suggesting uncertainty in the size of effect and caution in its interpretation. While physical activity appears to be a promising and acceptable intervention for adolescents and young adults experiencing depression, robust clinical effectiveness trials that minimise risk of bias are required to increase confidence in the current finding. The specific intervention characteristics required to improve depression remain unclear, however best candidates given current evidence may include, but are not limited to, supervised, aerobic-based activity of moderate-to-vigorous intensity, engaged in multiple times per week over eight or more weeks. Further research is needed. (Registration: PROSPERO-CRD 42015024388).

Substance use in youth at risk for psychosis.

BACKGROUND: People with schizophrenia have high rates of substance use which contributes to co-morbidity and premature mortality. Some evidence suggests people at-risk for psychosis have high rates of substance use. We aimed to assess substance use in a help-seeking cohort, comparing those at-risk and not at-risk for psychosis, and to establish any relationship with clinical symptoms. METHOD: Participants were help-seeking youth presenting to mental health services in Sydney and Melbourne. 279 (34.8%) were at-risk for psychosis, and 452 (56.4%) did not meet criteria for a psychotic disorder or risk for psychosis. The excluded individuals were made up of 59 (7.4%) young people who met criteria for a psychotic disorder and 11 (1.4%) who were unable to be evaluated. We assessed the association of substance use involvement with risk status and clinical symptoms using multivariate regression. RESULTS: Individuals at-risk for psychosis had significantly higher tobacco, alcohol and cannabis use than those not at-risk. Multivariate analysis revealed at-risk status was significantly associated with higher alcohol involvement scores when adjusting for age and gender, but no association was found for cannabis or tobacco. At-risk status was no longer associated with alcohol involvement when cannabis or tobacco use was added into the analysis. CONCLUSION: Tobacco smoking, alcohol consumption and cannabis use are common in help-seeking youth, particularly those at-risk for psychosis. It is important to consider co-occurring use of different substances in adolescents. Early substance misuse in this phase of illness could be targeted to improve physical and mental health in young people.

Self reported rates of criminal offending and victimization in young people at-risk for psychosis.

A significant relationship exists between experiencing psychosis and both engaging in criminal offending and being a victim of crime. A substantial proportion of violence and offending occurs during the first episode of psychosis, but it is unclear whether such behaviour is also evident in the earlier pre-psychotic stage of illness. As part of a prospective study of young people who were seeking help for mental health problems, we enquired about participants' experiences of being charged and/or convicted of a criminal offence and being a victim of crime. This paper uses cross-sectional baseline data to compare the rates of these forensic outcomes in participants at-risk of psychosis (n=271) with those not at-risk (n=440). Univariate logistic regression showed that the at-risk for psychosis group was significantly more likely than the not at-risk participants to report having been charged by police (11.1% vs 5.9%; p=.015) and convicted by the courts (4.4% vs. 1.6%; p=0.028) with a non-violent offence, as well as to have been convicted of any criminal offence (6.3% vs. 3.0%; p=0.037). The at-risk were also more likely to report having been a victim of crime (23.7% vs 14.0%; p=.002), particularly violent victimization (16.5% vs 8.2%; p=.001). In multivariate logistic regression analyses, being at-risk for psychosis remained a significant predictor of three of the four outcome measures after controlling for other known covariates such as gender, age, substance misuse and unemployment. This is the first study to demonstrate that, relative to their non-psychotic help-seeking counterparts, young people at-risk for psychosis are at higher risk of forensic outcomes, particularly violent crime victimization.

Transitions Study of predictors of illness progression in young people with mental ill health: study methodology.

AIM: An estimated 75% of mental disorders begin before the age of 24 and approximately 25% of 13-24-year-olds are affected by mental disorders at any one time. To better understand and ideally prevent the onset of post-pubertal mental disorders, a clinical staging model has been proposed that provides a longitudinal perspective of illness development. This heuristic model takes account of the differential effects of both genetic and environmental risk factors, as well as markers relevant to the stage of illness, course or prognosis. The aim of the Transitions Study is to test empirically the assumptions that underpin the clinical staging model. Additionally, it will permit investigation of a range of psychological, social and genetic markers in terms of their capacity to define current clinical stage or predict transition from less severe or enduring to more severe and persistent stages of mental disorder. METHOD: This paper describes the study methodology, which involves a longitudinal cohort design implemented within four headspace youth mental health services in Australia. Participants are young people aged 12-25 years who have sought help at headspace and consented to complete a comprehensive assessment of clinical state and psychosocial risk factors. A total of 802 young people (66% female) completed baseline assessments. Annual follow-up assessments have commenced. CONCLUSIONS: The results of this study may have implications for the way mental disorders are diagnosed and treated, and progress our understanding of the pathophysiologies of complex mental disorders by identifying genetic or psychosocial markers of illness stage or progression.

Limited hepatitis B virus replication space in the chronically hepatitis C virus-infected liver.

We compared the kinetics and magnitude of hepatitis B virus (HBV) infection in hepatitis C virus (HCV)-naive and chronically HCV-infected chimpanzees in whose livers type I interferon-stimulated gene (ISG) expression is strongly induced. HBV infection was delayed and attenuated in the HCV-infected animals, and the number of HBV-infected hepatocytes was drastically reduced. These results suggest that establishment of HBV infection and its replication space is limited by the antiviral effects of type I interferon in the chronically HCV-infected liver.

Serological evidence for a hepatitis e virus-related agent in goats in the United States.

Hepatitis E virus (HEV) causes an important public health disease in many developing countries and is also endemic in some industrialized countries. In addition to humans, strains of HEV have been genetically identified from pig, chicken, rat, mongoose, deer, rabbit and fish. While the genotypes 1 and 2 HEV are restricted to humans, the genotypes 3 and 4 HEV are zoonotic and infect humans and other animal species. As a part of our ongoing efforts to search for potential animal reservoirs for HEV, we tested goats from Virginia for evidence of HEV infection and showed that 16% (13/80) of goat sera from Virginia herds were positive for IgG anti-HEV. Importantly, we demonstrated that neutralizing antibodies to HEV were present in selected IgG anti-HEV positive goat sera. Subsequently, in an attempt to genetically identify the HEV-related agent from goats, we conducted a prospective study in a closed goat herd with known anti-HEV seropositivity and monitored a total of 11 kids from the time of birth until 14 weeks of age for evidence of HEV infection. Seroconversion to IgG anti-HEV was detected in seven of the 11 kids, although repeated attempts to detect HEV RNA by a broad-spectrum nested RT-PCR from the faecal and serum samples of the goats that had seroconverted were unsuccessful. In addition, we also attempted to experimentally infect laboratory goats with three well-characterized mammalian strains of HEV but with no success. The results indicate that a HEV-related agent is circulating and maintained in the goat population in Virginia and that the goat HEV is likely genetically very divergent from the known HEV strains.

Embracing performance measurement in mental health services.

OBJECTIVES: Performance measurement (PM) is central to the current Irish health service policy. However, PM within the Irish mental health services has not been fully implemented. These services lack a national comprehensive suite of performance indicators (PIs). Those indicators that are measured do not tend to reflect the objectives of the managers and staff measuring them. To overcome these challenges, this article suggests a suite of measures and aims to provide a practical guide to PM for managers and staff. METHOD: A narrative review of a range of policy documents and articles, relevant to PM in the Irish mental health services, was undertaken. Findings The search produced a number of themes illustrating the limitations of the current set of PIs for Irish mental health services, in particular the need for comprehensive PIs, including structure, process and outcome PIs. This informed the development of a suite of proposed PIs for mental health services. A number of additional themes highlighted the criticisms associated with the top-down approach used to implement PM. Drawing from these themes, a bottom-up approach to PM is proposed. CONCLUSION: Although this review was selective in nature, it illustrates how the concerns of clinicians and service managers can be integrated with the priorities of the Health Service Executive and the Department of Health. This presented the suite of PIs and the practical guide that provide useful PM tools. While also applicable at a national level, this paper provides guidance for service managers as to the process of establishing and implementing a suite of PIs within their own service.

Age of onset of mental disorders and use of mental health services: needs, opportunities and obstacles.

PURPOSE OF REVIEW: In this review, we provide an update of recent studies on the age of onset (AOO) of the major mental disorders, with a special focus on the availability and use of services providing prevention and early intervention. RECENT FINDINGS: The studies reviewed here confirm previous reports on the AOO of the major mental disorders. Although the behaviour disorders and specific anxiety disorders emerge during childhood, most of the high-prevalence disorders (mood, anxiety and substance use) emerge during adolescence and early adulthood, as do the psychotic disorders. Early AOO has been shown to be associated with a longer duration of untreated illness, and poorer clinical and functional outcomes. SUMMARY: Although the onset of most mental disorders usually occurs during the first three decades of life, effective treatment is typically not initiated until a number of years later. There is increasing evidence that intervention during the early stages of disorder may help reduce the severity and/or the persistence of the initial or primary disorder, and prevent secondary disorders. However, additional research is needed on effective interventions in early-stage cases, as well as on the long-term effects of early intervention, and for an appropriate service design for those with emerging mental disorders. This will mean not only the strengthening and re-engineering of existing systems, but is also crucial the construction of new streams of care for young people in transition to adulthood.

Quality of information sources about mental disorders: a comparison of Wikipedia with centrally controlled web and printed sources.

BACKGROUND: Although mental health information on the internet is often of poor quality, relatively little is known about the quality of websites, such as Wikipedia, that involve participatory information sharing. The aim of this paper was to explore the quality of user-contributed mental health-related information on Wikipedia and compare this with centrally controlled information sources. METHOD: Content on 10 mental health-related topics was extracted from 14 frequently accessed websites (including Wikipedia) providing information about depression and schizophrenia, Encyclopaedia Britannica, and a psychiatry textbook. The content was rated by experts according to the following criteria: accuracy, up-to-dateness, breadth of coverage, referencing and readability. RESULTS: Ratings varied significantly between resources according to topic. Across all topics, Wikipedia was the most highly rated in all domains except readability. CONCLUSIONS: The quality of information on depression and schizophrenia on Wikipedia is generally as good as, or better than, that provided by centrally controlled websites, Encyclopaedia Britannica and a psychiatry textbook.

Mutational analysis of the hepatitis C virus E1 glycoprotein in retroviral pseudoparticles and cell-culture-derived H77/JFH1 chimeric infectious virus particles.

Cell entry by enveloped viruses is mediated by viral glycoproteins, and generally involves a short hydrophobic peptide (fusion peptide) that inserts into the cellular membrane. An internal hydrophobic domain within E1 (aa262-290) of hepatitis C virus (HCV) may function as a fusion peptide. Retrovirus-based HCV-pseudotyped viruses (HCVpp; genotype 1a) containing Ala or Pro substitutions at conserved amino acid positions within this putative fusion peptide were generated. Mutation of conserved residues significantly reduced efficiency of HCVpp entry into Huh-7 cells. The majority of amino acid substitutions appeared to disrupt necessary interactions between E1 and E2. For some mutants, reductions in HCVpp-associated E1 were associated with the incorporation of a high molecular weight, hyperglycosylated E2 that displayed decreased CD81-binding. Other entry-deficient mutants displayed normal E1E2 incorporation into pseudoparticles and normal CD81-binding, and therefore might affect viral fusion. One mutant (S283P) consistently displayed two- to threefold higher infectivity than did wild-type. Three mutations that decreased HCVpp infectivity also reduced levels of HCVcc infectious virus production. However, the S283P mutation had a different effect in the two systems as it did not increase production of infectious HCVcc. This comprehensive mutational analysis of the putative HCV fusion peptide provides insight into the role of E1 in its interaction with E2 and in HCV entry.

Immunologic responses to therapeutic biologic agents.

Recombinant protein technology and the subsequent development of biologic agents for pharmacotherapy have greatly improved the treatment of a wide variety of diseases in humans. These products are subject to reactions not previously seen in other drug classes. Additionally, subtle alteration in the manufacture or administration of a biologic agent may cause reactions in subjects who previously tolerated it. This review highlights the unique immunologic reactions that are associated with the more commonly used biologic agents.

Early identification and intervention in depressive disorders: towards a clinical staging model.

BACKGROUND: Depressive disorders are common and associated risks include the onset of secondary disorders, substance use disorders, impairment in social and occupational functioning, and an increase in suicidality. As the onset often occurs in youth, there is a clear imperative for early identification and intervention to ameliorate, if not prevent, associated distress. METHODS: An extensive search of relevant databases and an ancestry search was undertaken. RESULTS: There is a limited but growing body of literature on this topic that is discussed in relation to a clinical staging model, which may prove to be a useful framework for identifying where an individual lies along the continuum of the course of a depressive illness thus allowing interventions to be matched for that stage. The identification of a subsyndromal and prodromal stage of depressive disorders provides early intervention opportunities. CONCLUSIONS: It is argued that a clinical staging heuristic may increase the number of those treated early, which may in turn delay or prevent onset, reduce severity, or prevent progression in the course of depressive disorders.

Hepatitis E: an emerging awareness of an old disease.

Although hepatitis E was recognized as a new disease in 1980, the virus was first visualized in 1983 and its genome was cloned and characterized in 1991, the disease is probably ancient but not recognized until modern times. Hepatitis E is the most important or the second most important cause of acute clinical hepatitis in adults throughout Asia, the Middle East and Africa. In contrast, hepatitis E is rare in industrialized countries, but antibody (anti-HEV) is found worldwide. HEV is a small round RNA-containing virus that is the only member of the genus Hepevirus in the family Hepeviridae. Although similar to hepatitis A virus in appearance, there are significant differences between the two viruses. Hepatitis E is principally the result of a water-borne infection in developing countries and is thought to be spread zoonotically (principally from swine) in industrialized countries. Because diagnostic tests vary greatly in specificity, sensitivity and availability, hepatitis E is probably underdiagnosed. At present, control depends upon improved hygiene; a highly efficacious vaccine has been developed and tested, but it is not presently available.