Using social innovation as a theoretical framework to guide future thinking on facilitating collaboration between mental health and criminal justice services.

Offender mental health is a major societal challenge. Improved collaboration between mental health and criminal justice services is required to address these challenges. This paper explores the potential social innovation as a concept that offers an alternative perspective on collaborations between these services and a framework to develop theoretically informed strategies to optimize interorganizational working. Two key innovation frameworks are applied to the offender mental health field and practice illustrations provided of where new innovations in collaboration, and specifically cocreation between the mental health system and criminal justice system, take place. The paper recommends the development of a competency framework for leaders and front line staff in the mental health system and criminal justice systems to raise awareness and skills in the innovation process, especially through cocreation across professional and organizational boundaries

On the evolution of clustering of 24um-selected galaxies

This paper investigates the clustering properties of a complete sample of 1041 24um-selected sources brighter than F[24um]=400 uJy in the overlapping region between the SWIRE and UKIDSS UDS surveys. We have concentrated on the two (photometric) interval ranges z=[0.6-1.2] (low-z sample) and z>1.6 (high-z sample) as it is in these regions were we expect the mid-IR population to be dominated by intense dust-enshrouded activity such as star formation and black hole accretion. Investigations of the angular correlation function produce a correlation length are r0~15.9 Mpc for the high-z sample and r0~8.5 Mpc for the low-z one. Comparisons with physical models reveal that the high-z sources are exclusively associated with very massive (M>~10^{13} M_sun)haloes, comparable to those which locally host groups-to-clusters of galaxies, and are very common within such (rare) structures. Conversely, lower-z galaxies are found to reside in smaller halos (M_min~10^{12} M_sun) and to be very rare in such systems. While recent studies have determined a strong evolution of the 24um luminosity function between z~2 and z~0, they cannot provide information on the physical nature of such an evolution. Our clustering results instead indicate that this is due to the presence of different populations of objects inhabiting different structures, as active systems at z<~1.5 are found to be exclusively associated with low-mass galaxies, while very massive sources appear to have concluded their active phase before this epoch. Finally, we note that the small-scale clustering data seem to require steep profiles for the distribution of galaxies within their halos. This is suggestive of close encounters and/or mergers which could strongly favour both AGN and star-formation activity.Comment: 13 pages, 8 figures, to appear in MNRA

The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue

Mutations in the presenilin 1 gene, PSEN1, which cause familial Alzheimer’s disease alter processing of amyloid precursor protein, leading to the generation of various amyloid-β peptide species. These species differ in their potential for aggregation. Mutation-specific amyloid-β peptide profiles may thereby influence pathogenicity and clinical heterogeneity. There is particular interest in comparing mutations with typical and atypical clinical presentations, such as E280G. We generated PSEN1 E280G mutation induced pluripotent stem cells from two patients and differentiated them into cortical neurons, along with previously reported PSEN1 M146I, PSEN1 R278I and two control lines. We assessed both the amyloid-β peptide profiles and presenilin 1 protein maturity. We also compared amyloid-β peptide profiles in human post-mortem brain tissue from cases with matched mutations. Amyloid-β ratios significantly differed compared with controls and between different patients, implicating mutation-specific alterations in amyloid-β ratios. Amyloid-β42:40 was increased in the M146I and both E280G lines compared with controls. Amyloid-β42:40 was not increased in the R278I line compared with controls. The amyloid-β43:40 ratio was increased in R278I and both E280G lines compared with controls, but not in M146I cells. Distinct amyloid-β peptide patterns were also observed in human brain tissue from individuals with these mutations, showing some similar patterns to cell line observations. Reduced presenilin 1 maturation was observed in neurons with the PSEN1 R278I and E280G mutations, but not the M146I mutation. These results suggest that mutation location can differentially alter the presenilin 1 protein and affect its autoendoproteolysis and processivity, contributing to the pathological phenotype. Investigating differences in underlying molecular mechanisms of familial Alzheimer’s disease may inform our understanding of clinical heterogeneity

Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer’s disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease

Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease.

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD

University teachers’ views of interprofessional learning and their role in achieving outcomes - a qualitative study

Over the past decade, there has been a rapid increase in higher education institutions offering opportunities for interprofessional learning (IPL) to their students. The literature presents a number of factors that contribute to effective IPL, including having trained facilitators that help optimise the learning process. Many of these IPL facilitators are university teachers and the literature provides us with some insight into their views of IPL. However, little is known about university teachers’ views about IPL and their role in supporting students in achieving outcomes linked to IPL during their own teaching; this paper explores these areas. University teachers, working with students in Norway and England who contribute to patients’ care pathway were purposively invited to join focus groups. Data collected from the teachers’ conversations during these focus groups were analysed to elicit the main themes. Findings show that university teachers have a wide range of views about IPL, its potential to enhance collaborative practice and care, and their role in helping students achieve outcomes linked to IPL. A key challenge appears to be whether IPL is “worth the struggle,” which emphasises the need for strong leadership in order to align pedagogical approaches in education and practice that strive to achieve agreed outcomes

Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding

&lt;p&gt;Introduction - Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.&lt;/p&gt; &lt;p&gt;Materials and Methods - Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.&lt;/p&gt; &lt;p&gt;Results - There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].&lt;/p&gt; &lt;p&gt;Conclusions - The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.&lt;/p&gt

Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides in disease pathogenesis, however less is known about the behaviour of these mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age- and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (p < 0.001) and non-carriers (p < 0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (p < 0.001) and non-carriers (p < 0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both p < 0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental age at onset. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein carriers provide insights into disease pathophysiology, which can inform therapy development

The PEP survey: clustering of infrared-selected galaxies and structure formation at z~2 in the GOODS South

ABRIDGED-This paper presents the first direct estimate of the 3D clustering properties of far-infrared sources up to z~3. This has been possible thanks to the Pacs Evolutionary Probe (PEP) survey of the GOODS South field performed with the PACS instrument onboard the Herschel Satellite. An analysis of the two-point correlation function over the whole redshift range spanned by the data reports for the correlation length, r_0~6.3 Mpc and r_0~6.7 Mpc, respectively at 100um and 160um, corresponding to dark matter halo masses M>~10^{12.4} M_sun. Objects at z~2 instead seem to be more strongly clustered, with r_0~19 Mpc and r_0~17 Mpc in the two considered PACS channels. This dramatic increase of the correlation length between z~1 and z~2 is connected with the presence of a wide, M>~10^{14} M_sun, filamentary structure which includes more than 50% of the sources detected at z~2. An investigation of the properties of such sources indicates the possibility for boosted star-forming activity in those which reside within the overdense environment with respect of more isolated galaxies found in the same redshift range. Lastly, we also present our results on the evolution of the relationship between luminous and dark matter in star-forming galaxies between z~1 and z~2. We find that the increase of (average) stellar mass in galaxies between z~1 and z~2 is about a factor 10 lower than that of the dark matter haloes hosting such objects ([z~1]/[z~2] ~ 0.4 vs M_{halo}[z~1]/M_{halo}[z~2] ~ 0.04). Our findings agree with the evolutionary picture of downsizing whereby massive galaxies at z~2 were more actively forming stars than their z~1 counterparts, while at the same time contained a lower fraction of their mass in the form of luminous matter.Comment: 14 pages, 8 figures, MNRAS accepte

The Magnitude and Kinetics of the Mucosal HIV-Specific CD8+ T Lymphocyte Response and Virus RNA Load in Breast Milk

BACKGROUND: The risk of postnatal HIV transmission is associated with the magnitude of the milk virus load. While HIV-specific cellular immune responses control systemic virus load and are detectable in milk, the contribution of these responses to the control of virus load in milk is unknown. METHODS: We assessed the magnitude of the immunodominant GagRY11 and subdominant EnvKY9-specific CD8+ T lymphocyte response in blood and milk of 10 A*3002+, HIV-infected Malawian women throughout the period of lactation and correlated this response to milk virus RNA load and markers of breast inflammation. RESULTS: The magnitude and kinetics of the HIV-specific CD8+ T lymphocyte responses were discordant in blood and milk of the right and left breast, indicating independent regulation of these responses in each breast. However, there was no correlation between the magnitude of the HIV-specific CD8+ T lymphocyte response and the milk virus RNA load. Further, there was no correlation between the magnitude of this response and markers of breast inflammation. CONCLUSIONS: The magnitude of the HIV-specific CD8+ T lymphocyte response in milk does not appear to be solely determined by the milk virus RNA load and is likely only one of the factors contributing to maintenance of low virus load in milk