Strategically using public housing assets could transform our middle suburbs

‘Greyfields’ in the Australian context have been defined as those ageing but occupied tracts of inner and middle ring suburbia that are physically, technologically and environmentally failing. The research sought to test the potential of an innovative design based approach to create coordinated precincts in these suburbs involving the coordinated redevelopment of multiple, non-contiguous public housing lots (rather than relying on the ‘default’ option of incremental market based development of in-fill housing and piecemeal selling off of public housing properties). Recent public housing investments (under the Social Housing Initiative) were typically planned with job creation in mind rather than innovative housing outcomes, but innovations were still apparent. Innovations were generally simple such as improvements to parking arrangements and interfaces of private dwellings with common areas and public spaces and arrangements for tenancy mix and social diversity. Innovations were often more apparent when governments partnered with Community Housing Organisations who could access alternative land and funding sources, offer design and delivery expertise and facilitate mixed tenancy outcomes. Innovation also was more likely when there was a ‘champion’ for design quality, relaxation of selected planning controls, and project alignment with existing urban renewal strategies. The Department of Human Services (Victorian Government) was found to have existing housing assets in sufficient number (more than 6500 DHS properties) in well-located areas of Melbourne’s middle suburbs that were clustered in ways broadly suitable for coordinated precinct redevelopment. Preliminary investigations suggest the same in Sydney and Brisbane. The coordinated precinct approach could offer an effective model for redeveloping dispersed public housing assets. Integrated redevelopment can achieve substantial increases in dwelling yield—design scenarios developed in this study delivered two to four times the number of dwellings when compared to business-as-usual dual occupancy outcomes. A precinct design approach is potentially more efficient because it allows for non-uniform, flexible siting of higher density buildings, effective program mixes, efficient parking arrangements and a variety of households and tenure types to be accommodated across a neighbourhood. Preliminary discussions with key stakeholders—municipal authorities, community housing organisations and local community members—showed real interest in the benefits of a coordinated precinct-based development approach. - See more at: http://www.ahuri.edu.au/publications/projects/p52012#sthash.wTtz4itu.dpu

Better post-operative prediction and management of chronic pain in adults after total knee replacement:the multidisciplinary STAR research programme including RCT

Background: The treatment of osteoarthritis with knee replacement aims to reduce pain and disability. However, some people experience chronic pain. Objectives: To improve outcomes for people with chronic pain after knee replacement by identifying post-surgical predictors and effective interventions, characterising patient pathways and resource use, developing and evaluating a new care pathway, and exploring non-use of services. Design: The programme comprised systematic reviews, national database analyses, a cohort study, intervention development, a randomised controlled trial, health economic analyses, qualitative studies and stakeholder engagement. Extensive and meaningful patient and public involvement underpinned all studies. Setting: NHS, secondary care, primary care. Participants: People with, or at risk of, chronic pain after knee replacement and health-care professionals involved in the care of people with pain. Interventions: A care pathway for the management of people with pain at 3 months after knee replacement. Main outcome measures: Patient-reported outcomes and cost-effectiveness over 12 months. Data sources: Literature databases, the National Joint Registry, Hospital Episode Statistics, patient- reported outcomes, the Clinical Practice Research Datalink, the Clinical Outcomes in Arthroplasty Study, the Support and Treatment After joint Replacement randomised trial, interviews with 90 patients and 14 health-care professionals, and stakeholder events. Review methods: Systematic reviews of cohort studies or randomised trials, using meta-analysis or narrative synthesis. Results: In the Clinical Outcomes in Arthroplasty Study cohort, 14% of people experienced chronic pain 1 year after knee replacement. By 5 years, 65% reported no pain, 31% fluctuated and 4% remained in chronic pain. People with chronic pain had a worse quality of life, higher primary care costs, and more frequent analgesia prescriptions, particularly for opioids, than those not in chronic pain. People with chronic pain after knee replacement who made little or no use of services often felt nothing more could be done, or that further treatments may have no benefit or cause harm. People described a feeling of disconnection from their replaced knee. Analysis of UK databases identified risk factors for chronic pain after knee replacement. Pre- operative predictors were mild knee pain, smoking, deprivation, body mass index between 35 and 40 kg/m2 and knee arthroscopy. Peri- and post-operative predictors were mechanical complications, infection, readmission, revision, extended hospital stay, manipulation under anaesthetic and use of opioids or antidepressants. In systematic reviews, pre-operative exercise and education showed no benefit in relation to chronic pain. Peri-operative interventions that merit further research were identified. Common peri- operative treatments were not associated with chronic pain. There was no strong evidence favouring specific post-operative physiotherapy content. We evaluated the Support and Treatment After joint Replacement care pathway in a multicentre randomised controlled trial. We randomised 363 people with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales. At 12 months’ follow-up, the intervention group had lower mean pain severity (adjusted difference –0.65, 95% confidence interval –1.17 to -0.13; p = 0.014) and pain interference (adjusted difference –0.68, 95% confidence interval –1.29 to -0.08; p = 0.026), as measured on the Brief Pain Inventory subscales (scale 0–10). People receiving the Support and Treatment After joint Replacement pathway had lower NHS and Personal Social Services costs (–£724, 95% confidence interval –£150 to £51) and higher quality-adjusted life-years (0.03, 95% confidence interval –0.008 to 0.06) than those with usual care. The Support and Treatment After joint Replacement pathway was cost-effective with an incremental net monetary benefit at the £20,000 per quality-adjusted life-year threshold of £1256 (95% confidence interval £164 to £2348), indicating a 98.79% probability that the intervention is the cost-effective option. Participants found the Support and Treatment After joint Replacement pathway acceptable, with opportunities to receive information and discuss concerns while ensuring further treatment and support. In systematic reviews considering treatments for chronic pain after surgery we identified some unifactorial interventions that merit further research after knee replacement. Health-care professionals delivering and implementing the Support and Treatment After joint Replacement pathway valued its focus on neuropathic pain and psychosocial issues, enhanced patient care, formalised referrals, and improved pain management. Stakeholders supported pathway implementation. Limitations: Database analyses were limited to factors recorded in data sets. Pain was only measured 6 months after surgery. However, analyses including large numbers of centres and patients should be generalisable across the NHS. In many studies found in systematic reviews, long-term pain was not a key outcome. Conclusions: The Support and Treatment After joint Replacement pathway is a clinically effective and cost-effective, acceptable intervention for the management of chronic pain after knee replacement. Unifactorial interventions merit further study before inclusion in patient care. People with pain should be empowered to seek health care, with the support of health-care professionals. Future work: Future work should include research relating to the implementation of the Support and Treatment After joint Replacement pathway into the NHS, an assessment of its long-term clinical effectiveness and cost-effectiveness and wider application, and an evaluation of new interventions for incorporation in the pathway. It will also be important to design and conduct research to improve communication between patients and health-care professionals before surgery; explore whether or not education and support can enable earlier recognition of chronic pain; consider research that may identify how to support people’s feelings of disconnectedness from their new knee; and design and evaluate a pre-surgical intervention based on risk factors. Study registration: All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The Support and Treatment After joint Replacement randomised trial was registered as ISRCTN92545361. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information

Metabolic engineering of Clostridium autoethanogenum for selective alcohol production

Gas fermentation using acetogenic bacteria such as Clostridium autoethanogenum offers an attractive route for production of fuel ethanol from industrial waste gases. Acetate reduction to acetaldehyde and further to ethanol via an aldehyde: ferredoxin oxidoreductase (AOR) and alcohol dehydrogenase has been postulated alongside the classic pathway of ethanol formation via a bi-functional aldehyde/alcohol dehydrogenase (AdhE). Here we demonstrate that AOR is critical to ethanol formation in acetogens and inactivation of AdhE led to consistently enhanced autotrophic ethanol production (up to 180%). Using ClosTron and allelic exchange mutagenesis, which was demonstrated for the first time in an acetogen, we generated single mutants as well as double mutants for both aor and adhE isoforms to confirm the role of each gene. The aor1+2 double knockout strain lost the ability to convert exogenous acetate, propionate and butyrate into the corresponding alcohols, further highlighting the role of these enzymes in catalyzing the thermodynamically unfavourable reduction of carboxylic acids into alcohols

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies