The association between area-level factors and mortality in severe mental illnesses: A systematic review.

BACKGROUND: Premature mortality is a well-documented adverse outcome for people living with severe mental illnesses (SMI). Emerging evidence suggests that area-level factors play a role that are experienced disproportionately by this population. This review assesses the potential association between area-level factors and mortality in people with SMI. METHOD: We searched Medline, EMBASE, PsychINFO, Social Policy and Practice, Web of Science and OpenGrey databases. Literature searches were conducted in May 2020 and updated in June 2023. Reference lists were hand-searched and authors of included studies contacted to identify additional studies and minimise publication biases. Narrative synthesis was used to appraise the included studies. The review protocol was registered on PROSPERO (CRD42019155447). RESULTS: Our searches identified 7 studies (8 papers), which were included in the review, and indicated evidence of an association between deprivation and mortality. One study suggested an association between mortality in SMI and urbanicity in low to middle income settings which was not observed in studies from high income settings. One study suggested a protective association of area-level ethnic density with mortality within urbanised settings. CONCLUSION: Consistent associations were reported between residence in areas of higher deprivation and increased risk of mortality in SMI. Two studies suggested an association between area-level ethnic density and urbanicity and mortality in SMI. Most studies were conducted across high income countries and therefore future research could benefit from similar investigations being conducted in low- and middle-income countries. These methods would inform health and social policies, including interventions to reduce premature mortality in SMI.

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Healthcare Costs Before and After Diagnosis of Cancer of Unknown Primary Versus Ovarian Cancer in Australia.

BACKGROUND: Little is known about the healthcare resource usage and costs for patients with cancer of unknown primary (CUP). OBJECTIVE: The aim of this study was to describe and quantify healthcare resource use and costs in Australia, 6 months prior to and after a diagnosis of CUP, and compare to those of women with ovarian cancer. METHODS: Individual-level data combining baseline surveys, clinical records and Medicare Benefits Schedule (MBS) claim records were analysed for 149 patients with CUP and 480 patients with ovarian cancer from two prospective cohort studies. MBS data were aggregated for the period 6 months prior to diagnosis date and 6 months after diagnosis. Data included doctor consultations, pathology, diagnostics, therapeutic procedures, imaging, allied health and medicines. Generalised linear models were used to evaluate the cost differences between CUP and ovarian cancer using gamma family and log link functions. Models were adjusted for age, employment, marital status, surgery, chemotherapy and number of comorbidities. RESULTS: The mean healthcare costs in the 6 months prior to diagnosis of CUP were Australian (AU) $3903 versus AU$1327 for ovarian cancer (adjusted cost ratio 2.94, 95% confidence interval [CI] 2.08-4.15). Mean healthcare costs 6 months post-diagnosis were higher for patients with CUP versus ovarian cancer (AU$20,339 vs AU$13,819, adjusted cost ratio 1.47, 95% CI 1.13-1.92). Higher costs for patients with CUP were driven by imaging (AU$1937 vs AU$1387), procedures (AU$5403 vs AU$2702) and prescribed medicines for all conditions (AU$10,111 vs AU$6717). CONCLUSIONS: Pre-diagnosis costs for patients with CUP are nearly triple those for ovarian cancer. Six months after diagnosis, healthcare costs for CUP remained higher than for ovarian cancer due to imaging, procedures and medicines.

Chronic pain through COVID.

Objectives: To identify good practice in the community management of chronic pain, and to understand the perspective of a group of healthcare service users towards the management of chronic pain using technology during the COVID-19 pandemic. Methods: Forty-five people, recruited via social media and Pain Association Scotland, participated in three focus groups hosted over Zoom. Focus groups were conducted using semi-structured questions to guide the conversation. Data were analysed using Ritchie / Spencer's Framework Analysis. Results: The participants shared observations of their experiences of remotely supported chronic pain services and insights into the potential for future chronic pain care provision. Experiences were in the majority positive with some describing their rapid engagement with technology during the COVID pandemic. Conclusion: Results suggest there is strong potential for telehealth to complement and support existing provision of pain management services.

A nurse- and peer-led psycho-educational intervention to support women with gynaecological cancers receiving curative radiotherapy: The PeNTAGOn randomised controlled trial - ANZGOG 1102.

OBJECTIVE: Radiotherapy for gynaecological cancer is associated with multiple adverse effects. This randomised controlled trial evaluated the impact of a combined nurse- and peer-led psycho-educational intervention on psychological distress, preparation for treatment, quality of life, psychosexual function, unmet needs and vaginal stenosis. METHODS: Eligible women had a confirmed diagnosis of gynaecological cancer, scheduled to receive radiotherapy with curative intent, aged ≥18 years, and able to read and write English. Participants randomly assigned one-to-one to either four nurse-led consultations plus four peer-led telephone sessions, or to usual care. Participants completed study measures at baseline, immediately before first radiotherapy (FU1), and four weeks (FU2), three (FU3), six (FU4), and 12 months (FU5) post radiotherapy. The primary outcomes were psychological distress at FU1 and FU2 measured by the Hospital Anxiety and Depression Scale. RESULTS: Of 840 eligible participants, 625 were approached and 319 (51%) consented; 158 assigned to intervention, 160 to usual care with 1 withdrawing before randomisation. Between-groups differences for primary outcomes were trivial- and small-sized, (both p > 0.05). Notable effects on secondary outcomes favouring the intervention at FU2 included preparation for treatment (sensory/psychological concerns, d = 0.57; and procedural concerns, d = 0.52) and specific needs domains (sexuality needs, d = 0.38; and health system and information needs, d = 0.41). CONCLUSIONS: There was no evidence that a nurse- and peer-led intervention had a beneficial effect on psychological distress compared to usual care. However, improved treatment readiness and lower health system and sexuality needs indicate the intervention may have addressed outcomes known to be important to this population.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.

Outcomes and outcome measures used in evaluation of communication training in oncology - a systematic literature review, an expert workshop, and recommendations for future research.

BACKGROUND: Communication between health care provider and patients in oncology presents challenges. Communication skills training have been frequently developed to address those. Given the complexity of communication training, the choice of outcomes and outcome measures to assess its effectiveness is important. The aim of this paper is to 1) perform a systematic review on outcomes and outcome measures used in evaluations of communication training, 2) discuss specific challenges and 3) provide recommendations for the selection of outcomes in future studies. METHODS: To identify studies and reviews reporting on the evaluation of communication training for health care professionals in oncology, we searched seven databases (Ovid MEDLINE, CENTRAL, CINAHL, EMBASE, PsychINFO, PsychARTICLES and Web of Science). We extracted outcomes assessed and the respective assessment methods. We held a two-day workshop with experts (n = 16) in communication theory, development and evaluation of generic or cancer-specific communication training and/or outcome measure development to identify and address challenges in the evaluation of communication training in oncology. After the workshop, participants contributed to the development of recommendations addressing those challenges. RESULTS: Out of 2181 references, we included 96 publications (33 RCTs, 2 RCT protocols, 4 controlled trials, 36 uncontrolled studies, 21 reviews) in the review. Most frequently used outcomes were participants' training evaluation, their communication confidence, observed communication skills and patients' overall satisfaction and anxiety. Outcomes were assessed using questionnaires for participants (57.3%), patients (36.0%) and observations of real (34.7%) and simulated (30.7%) patient encounters. Outcomes and outcome measures varied widely across studies. Experts agreed that outcomes need to be precisely defined and linked with explicit learning objectives of the training. Furthermore, outcomes should be assessed as broadly as possible on different levels (health care professional, patient and interaction level). CONCLUSIONS: Measuring the effects of training programmes aimed at improving health care professionals' communication skills presents considerable challenges. Outcomes as well as outcome measures differ widely across studies. We recommended to link outcome assessment to specific learning objectives and to assess outcomes as broadly as possible.

Pain in older adults with dementia : A survey across Europe on current practices, use of assessment tools, guidelines and policies.

BACKGROUND: We aimed to explore the existing use of pain assessment tools and guidelines, and develop understanding of the practical considerations required to facilitate their use within the nursing home, hospital and community settings. METHODS: A self-administered web-based survey was conducted with nurses, health and social care workers with an interest in the assessment of pain in older adults with cognitive impairment. The survey was distributed to participants in Austria, Belgium, Denmark, Germany, The Netherlands, Switzerland and United Kingdom. RESULTS: Only a minority of staff reported use of (inter-)national or local standards or specific pain assessment tools in daily practice. A range of tools were reported as being used, which varied across country. While participants generally reported that these pain assessment tools were easy/very easy to use, many participants reported that they were difficult to interpret. Assessment is generally performed whilst providing nursing care. This was highlighted in 70-80% of all participating countries. While many of these tools rely on facial expression of pain, facial expressions were considered to be the least useful in comparison to other items. Furthermore findings showed that nurses employed in long-term care settings did not feel that they were educated enough in pain assessment and management. CONCLUSION: Our findings suggest that pain education is required across all countries surveyed. This should include a focus on guidelines and standards for assessment and subsequent management of pain. Findings suggest that clinical staff find interpreting facial expressions in relation to pain more difficult.

The modified Memorial Symptom Assessment Scale Short Form: a modified response format and rational scoring rules.

PURPOSE: The Memorial Symptom Assessment Scale Short Form (MSAS-SF) is a widely used symptom assessment instrument. Patients who self-complete the MSAS-SF have difficulty following the two-part response format, resulting in incorrectly completed responses. We describe modifications to the response format to improve useability, and rational scoring rules for incorrectly completed items. METHODS: The modified MSAS-SF was completed by 311 women in our Peer and Nurse support Trial to Assist women in Gynaecological Oncology; the PeNTAGOn study. Descriptive statistics were used to summarise completion of the modified MSAS-SF, and provide symptom statistics before and after applying the rational scoring rules. Spearman's correlations with the Functional Assessment for Cancer Therapy-General (FACT-G) and Hospital Anxiety and Depression Scale (HADS) were assessed. RESULTS: Correct completion of the modified MSAS-SF items ranged from 91.5 to 98.7%. The rational scoring rules increased the percentage of useable responses on average 4% across all symptoms. MSAS-SF item statistics were similar with and without the scoring rules. The pattern of correlations with FACT-G and HADS was compatible with prior research. CONCLUSION: The modified MSAS-SF was useable for self-completion and responses demonstrated validity. The rational scoring rules can minimise loss of data from incorrectly completed responses. Further investigation is recommended.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

Depression and pain: primary data and meta-analysis among 237 952 people across 47 low- and middle-income countries.

BACKGROUND: Depression and pain are leading causes of global disability. However, there is a paucity of multinational population data assessing the association between depression and pain, particularly among low- and middle-income countries (LMICs) where both are common. Therefore, we investigated this association across 47 LMICs. METHODS: Community-based data on 273 952 individuals from 47 LMICs were analysed. Multivariable logistic and linear regression analyses were performed to assess the association between the International Classification of Diseases, 10th Revision depression/depression subtypes (over the past 12 months) and pain in the previous 30 days based on self-reported data. Country-wide meta-analysis adjusting for age and sex was also conducted. RESULTS: The prevalence of severe pain was 8.0, 28.2, 20.2, and 34.0% for no depression, subsyndromal depression, brief depressive episode, and depressive episode, respectively. Logistic regression adjusted for socio-demographic variables, anxiety and chronic medical conditions (arthritis, diabetes, angina, asthma) demonstrated that compared with no depression, subsyndromal depression, brief depressive episode, and depressive episode were associated with a 2.16 [95% confidence interval (CI) 1.83-2.55], 1.45 (95% CI 1.22-1.73), and 2.11 (95% CI 1.87-2.39) increase in odds of severe pain, respectively. Similar results were obtained when a continuous pain scale was used as the outcome. Depression was significantly associated with severe pain in 44/47 countries with a pooled odds ratio of 3.93 (95% CI 3.54-4.37). CONCLUSION: Depression and severe pain are highly comorbid across LMICs, independent of anxiety and chronic medical conditions. Whether depression treatment or pain management in patients with comorbid pain and depression leads to better clinical outcome is an area for future research.

Type 2 diabetes mellitus in people with severe mental illness: inequalities by ethnicity and age. Cross-sectional analysis of 588 408 records from the UK.

AIMS: To investigate whether the association of severe mental illness with Type 2 diabetes varies by ethnicity and age. METHODS: We conducted a cross-sectional analysis of data from an ethnically diverse sample of 588 408 individuals aged ≥18 years, registered to 98% of general practices (primary care) in London, UK. The outcome of interest was prevalent Type 2 diabetes. RESULTS: Relative to people without severe mental illness, the relative risk of Type 2 diabetes in people with severe mental illness was greatest in the youngest age groups. In the white British group the relative risks were 9.99 (95% CI 5.34, 18.69) in those aged 18-34 years, 2.89 (95% CI 2.43, 3.45) in those aged 35-54 years and 1.16 (95% CI 1.04, 1.30) in those aged ≥55 years, with similar trends across all ethnic minority groups. Additional adjustment for anti-psychotic prescriptions only marginally attenuated the associations. Assessment of estimated prevalence of Type 2 diabetes in severe mental illness by ethnicity (absolute measures of effect) indicated that the association between severe mental illness and Type 2 diabetes was more marked in ethnic minorities than in the white British group with severe mental illness, especially for Indian, Pakistani and Bangladeshi individuals with severe mental illness. CONCLUSIONS: The relative risk of Type 2 diabetes is elevated in younger populations. Most associations persisted despite adjustment for anti-psychotic prescriptions. Ethnic minority groups had a higher prevalence of Type 2 diabetes in the presence of severe mental illness. Future research and policy, particularly with respect to screening and clinical care for Type 2 diabetes in populations with severe mental illness, should take these findings into account.

Minority status and mental distress: a comparison of group density effects.

BACKGROUND: It has been observed that mental disorders, such as psychosis, are more common for people in some ethnic groups in areas where their ethnic group is less common. We set out to test whether this ethnic density effect reflects minority status in general, by looking at three situations where individual characteristics differ from what is usual in a locality. METHOD: Using data from the South East London Community Health study (n = 1698) we investigated associations between minority status (defined by: ethnicity, household status and occupational social class) and risk of psychotic experiences, common mental disorders and parasuicide. We used a multilevel logistic model to examine cross-level interactions between minority status at individual and neighbourhood levels. RESULTS: Being Black in an area where this was less common (10%) was associated with higher odds of psychotic experiences [odds ratio (OR) 1.34 95% confidence interval (CI) 1.07-1.67], and attempted suicide (OR 1.84 95% CI 1.19-2.85). Living alone where this was less usual (10% less) was associated with increased odds of psychotic experiences (OR 2.18 95% CI 0.91-5.26), while being in a disadvantaged social class where this was less usual (10% less) was associated with increased odds of attempted suicide (OR 1.33 95% CI 1.03-1.71). We found no evidence for an association with common mental disorders. CONCLUSIONS: The relationship between minority status and mental distress was most apparent when defined in terms of broad ethnic group but was also observed for individual household status and occupational social class.

Approaches to Investigating Complex Genetic Traits in a Large-Scale Inbred Mouse Aging Study.

Inbred mice are a unique model system for studying aging because of the genetic homogeneity within inbred strains, the short life span of mice relative to humans, and the rich array of analytic tools that are available. A large-scale aging study was conducted on 28 inbred strains representing great genetic diversity to determine, via histopathology, the type and diversity of spontaneous diseases that aging mice develop. A total of 20 885 different diagnoses were made, with an average of 12 diagnoses per mouse in the study. Eighteen inbred strains have had their genomes sequenced, and many others have been partially sequenced to provide large repositories of data on genetic variation among the strains. This vast amount of genomic information can be utilized in genome-wide association studies to find candidate genes that are involved in the pathogenesis of spontaneous diseases. As an illustration, this article presents a genome-wide association study of the genetic associations of age-related intestinal amyloidosis, which implicated 3 candidate genes: translocating chain-associated membrane protein 1 (Tram1); splicing factor 3b, subunit 5 (Sf3b5); and syntaxin 11 (Stx11). Representative photomicrographs are available on the Mouse Tumor Biology Database and Pathbase to serve as a reference when evaluating inbred mice used in other genetic or experimental studies to rule out strain background lesions. Many of the age-related mouse diseases are similar, if not identical, to human diseases; therefore, the genetic discoveries have direct translational benefit.

Ethnicity and cardiovascular health inequalities in people with severe mental illnesses: protocol for the E-CHASM study.

PURPOSE: People with severe mental illnesses (SMI) experience a 17- to 20-year reduction in life expectancy. One-third of deaths are due to cardiovascular disease. This study will establish the relationship of SMI with cardiovascular disease in ethnic minority groups (Indian, Pakistani, Bangladeshi, black Caribbean, black African and Irish), in the UK. METHODS: E-CHASM is a mixed methods study utilising data from 1.25 million electronic patient records. Secondary analysis of routine patient records will establish if differences in cause-specific mortality, cardiovascular disease prevalence and disparities in accessing healthcare for ethnic minority people living with SMI exist. A nested qualitative study will be used to assess barriers to accessing healthcare, both from the perspectives of service users and providers. RESULTS: In primary care, 993,116 individuals, aged 18+, provided data from 186/189 (98 %) practices in four inner-city boroughs (local government areas) in London. Prevalence of SMI according to primary care records, ranged from 1.3-1.7 %, across boroughs. The primary care sample included Bangladeshi [n = 94,643 (10 %)], Indian [n = 6086 (6 %)], Pakistani [n = 35,596 (4 %)], black Caribbean [n = 45,013 (5 %)], black African [n = 75,454 (8 %)] and Irish people [n = 13,745 (1 %)]. In the secondary care database, 12,432 individuals with SMI over 2007-2013 contributed information; prevalent diagnoses were schizophrenia [n = 6805 (55 %)], schizoaffective disorders [n = 1438 (12 %)] and bipolar affective disorder [n = 4112 (33 %)]. Largest ethnic minority groups in this sample were black Caribbean [1432 (12 %)] and black African (1393 (11 %)). CONCLUSIONS: There is a dearth of research examining cardiovascular disease in minority ethnic groups with severe mental illnesses. The E-CHASM study will address this knowledge gap.

Does depression diagnosis and antidepressant prescribing vary by location? Analysis of ethnic density associations using a large primary-care dataset.

BACKGROUND: Studies have linked ethnic differences in depression rates with neighbourhood ethnic density although results have not been conclusive. We looked at this using a novel approach analysing whole population data covering just over one million GP patients in four London boroughs. METHOD: Using a dataset of GP records for all patients registered in Lambeth, Hackney, Tower Hamlets and Newham in 2013 we investigated new diagnoses of depression and antidepressant use for: Indian, Pakistani, Bangladeshi, black Caribbean and black African patients. Neighbourhood effects were assessed independently of GP practice using a cross-classified multilevel model. RESULTS: Black and minority ethnic groups are up to four times less likely to be newly diagnosed with depression or prescribed antidepressants compared to white British patients. We found an inverse relationship between neighbourhood ethnic density and new depression diagnosis for some groups, where an increase of 10% own-ethnic density was associated with a statistically significant (p < 0.05) reduced odds of depression for Pakistani [odds ratio (OR) 0.81, 95% confidence interval (CI) 0.70-0.93], Indian (OR 0.88, CI 0.81-0.95), African (OR 0.88, CI 0.78-0.99) and Bangladeshi (OR 0.94, CI 0.90-0.99) patients. Black Caribbean patients, however, showed the opposite effect (OR 1.26, CI 1.09-1.46). The results for antidepressant use were very similar although the corresponding effect for black Caribbeans was no longer statistically significant (p = 0.07). CONCLUSION: New depression diagnosis and antidepressant use was shown to be less likely in areas of higher own-ethnic density for some, but not all, ethnic groups.

The Vital Role of Pathology in Improving Reproducibility and Translational Relevance of Aging Studies in Rodents.

Pathology is a discipline of medicine that adds great benefit to aging studies of rodents by integrating in vivo, biochemical, and molecular data. It is not possible to diagnose systemic illness, comorbidities, and proximate causes of death in aging studies without the morphologic context provided by histopathology. To date, many rodent aging studies do not utilize end points supported by systematic necropsy and histopathology, which leaves studies incomplete, contradictory, and difficult to interpret. As in traditional toxicity studies, if the effect of a drug, dietary treatment, or altered gene expression on aging is to be studied, systematic pathology analysis must be included to determine the causes of age-related illness, moribundity, and death. In this Commentary, the authors discuss the factors that should be considered in the design of aging studies in mice, with the inclusion of robust pathology practices modified after those developed by toxicologic and discovery research pathologists. Investigators in the field of aging must consider the use of histopathology in their rodent aging studies in this era of integrative and preclinical geriatric science (geroscience).

Sustaining large-scale infrastructure to promote pre-competitive biomedical research: lessons from mouse genomics.

Bio-repositories and databases for biomedical research enable the efficient community-wide sharing of reagents and data. These archives play an increasingly prominent role in the generation and dissemination of bioresources and data essential for fundamental and translational research. Evidence suggests, however, that current funding and governance models, generally short-term and nationally focused, do not adequately support the role of archives in long-term, transnational endeavours to make and share high-impact resources. Our qualitative case study of the International Knockout Mouse Consortium and the International Mouse Phenotyping Consortium examines new governance mechanisms for archive sustainability. Funders and archive managers highlight in interviews that archives need stable public funding and new revenue-generation models to be sustainable. Sustainability also requires archives, journal publishers, and funders to implement appropriate incentives, associated metrics, and enforcement mechanisms to ensure that researchers use archives to deposit reagents and data to make them publicly accessible for academia and industry alike.

Genome-wide analysis implicates microRNAs and their target genes in the development of bipolar disorder.

Bipolar disorder (BD) is a severe and highly heritable neuropsychiatric disorder with a lifetime prevalence of 1%. Molecular genetic studies have identified the first BD susceptibility genes. However, the disease pathways remain largely unknown. Accumulating evidence suggests that microRNAs, a class of small noncoding RNAs, contribute to basic mechanisms underlying brain development and plasticity, suggesting their possible involvement in the pathogenesis of several psychiatric disorders, including BD. In the present study, gene-based analyses were performed for all known autosomal microRNAs using the largest genome-wide association data set of BD to date (9747 patients and 14 278 controls). Associated and brain-expressed microRNAs were then investigated in target gene and pathway analyses. Functional analyses of miR-499 and miR-708 were performed in rat hippocampal neurons. Ninety-eight of the six hundred nine investigated microRNAs showed nominally significant P-values, suggesting that BD-associated microRNAs might be enriched within known microRNA loci. After correction for multiple testing, nine microRNAs showed a significant association with BD. The most promising were miR-499, miR-708 and miR-1908. Target gene and pathway analyses revealed 18 significant canonical pathways, including brain development and neuron projection. For miR-499, four Bonferroni-corrected significant target genes were identified, including the genome-wide risk gene for psychiatric disorder CACNB2. First results of functional analyses in rat hippocampal neurons neither revealed nor excluded a major contribution of miR-499 or miR-708 to dendritic spine morphogenesis. The present results suggest that research is warranted to elucidate the precise involvement of microRNAs and their downstream pathways in BD.