Cost implications of treatment non-completion in a forensic personality disorder service

Background A high proportion of individuals admitted to specialist secure hospital services for treatment of personality disorder do not complete treatment. Non-completion has been associated with poorer treatment outcomes and increased rates of recidivism and hospital readmission, when compared with individuals who do complete treatment or who do not receive treatment at all. Aims In this study, we sought to determine the economic consequences of non-completion of treatment, using case study data from a secure hospital sample. Both health and criminal justice service perspectives were taken into account. Methods Data were collected from a medium secure hospital personality disorder unit. A probabilistic decision-analytic model was constructed, using a Markov cohort simulation with 10,000 iterations. The expected cost differential between those who do and those who do not complete treatment was estimated, as was the probability of a cost differential over a 10-year post-admission time horizon. Results On average, in the first 10 years following admission, those who do not complete treatment go on to incur £52,000 more in costs to the National Health Service and criminal justice system than those who complete treatment. The model estimates that the probability that non-completers incur greater costs than completers is 78%. Conclusion It is possible that an improvement in treatment completion rates in secure hospital personality disorder units would lead to some cost savings. This might be achievable through better selection into treatment or improved strategies for engagement and retention. Our study highlights a financial cost to society of individuals discharged from secure hospital care when incompletely treated. We suggest that it could, therefore, be useful for secure hospitals to introduce routine monitoring of treatment completion

CNS Remyelination and the Innate Immune System.

A misguided inflammatory response is frequently implicated in myelin damage. Particularly prominent among myelin diseases, multiple sclerosis (MS) is an autoimmune condition, with immune-mediated damage central to its etiology. Nevertheless, a robust inflammatory response is also essential for the efficient regeneration of myelin sheaths after such injury. Here, we discuss the functions of inflammation that promote remyelination, and how these have been experimentally disentangled from the pathological facets of the immune response. We focus on the contributions that resident microglia and monocyte-derived macrophages make to remyelination and compare the roles of these two populations of innate immune cells. Finally, the current literature is framed in the context of developing therapies that manipulate the innate immune response to promote remyelination in clinical myelin disease.The authors would particularly like to acknowledge the support of the UK MS Society, The Jean Shanks Foundation and MedImmune.This is the author accepted manuscript. The final version is available from Frontiers via http://dx.doi.org/10.3389/fcell.2016.0003

Regulatory T cells limit age-associated retinal inflammation and neurodegeneration

Ageing; Neurodegeneration; RetinaEnvejecimiento; Neurodegeneración; RetinaEnvelliment; Neurodegeneració; RetinaBackground Ageing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Methods Regulatory T cells were selectively depleted in both young (2–4 months) and aged (18–23 months) FoxP3-DTR mice. We evaluated neuroretinal degeneration, gliosis, subretinal space phagocyte infiltration, and retinal pigmented epithelium morphology through immunofluorescence analysis. Subsequently, aged Treg depleted animals underwent adoptive transfer of both young and aged regulatory T cells from wild-type mice, and the resulting impact on neurodegeneration was assessed. Statistical analyses employed included the U-Mann Whitney test, and for comparisons involving more than two groups, 1-way ANOVA analysis followed by Bonferroni’s post hoc test. Results Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. Conclusion Our findings demonstrate an essential role for regulatory T cells in maintaining age retinal homeostasis and preventing age-related neurodegeneration. This previously undescribed role of regulatory T cells in limiting retinal inflammation, RPE/choroid epithelium damage and subsequently photoreceptor loss with age, opens novel avenues to explore regulatory T cell neuroprotective and anti-inflammatory properties as potential therapeutic approaches for age-related retinal diseases.This work was supported by the Wellcome (110138/Z/15/Z to DCF), ECTRIMS postdoctoral fellowship (to AGF), Wellcome Trust ISSF fellowship through QUB (to AGF), Miguel Servet Fellowship from the Spanish Institute of Health Carlos III (CP21/00032 to AGF), The Leverhulme Trust (ECF-2014–390, to YD), the Maria Zambrano fellowship from Spanish Ministry of Science, Innovation and Universities, financed by European Union “NextGenerationEU” (Universitat Autònoma de Barcelona, to MLS), and H2020 RECOGNISED, European Commission and Fight for Sight UK Grant Agreement N° 847749 (to AS)

Exploratory analysis of biological age measures in a remyelination clinical trial

Enhancing CNS myelin repair (remyelination) is a promising strategy to prevent neurodegeneration and associated progressive disability in multiple sclerosis. Remyelination becomes inefficient with older chronological age, but the relationship between measures of biological age and remyelination has not been previously described in a clinical cohort. Here, we investigated two measures of biological age amongst participants of the Cambridge Centre for Myelin Repair One trial of bexarotene: MRI brain age (BAMRI) and a blood-based biological age (BABlood). In people with radiologically stable multiple sclerosis (n = 44 of 49 total participants), we found that treatment with bexarotene, along with promoting remyelination, was associated with significant decrease in MRI brain age [−1.98 years, 95% confidence interval (CI) [−3.75, −0.21 years] versus placebo over 6 months, P = 0.034]. Whilst BAMRI increased as expected during the trial in the placebo group (+0.92 years, CI [−0.41, 2.26]), the brain MRIs of participants treated with bexarotene appeared on average 11 months younger at the end compared to the start of the trial (−0.93 years, CI [−2.02, 0.17]). The effect of bexarotene on BAMRI was associated with its remyelinating activity in cortical grey matter lesions (β = 0.25% units (pu)/year, CI [0.03, 0.46], P = 0.023) and brainstem lesions (β = 0.24 pu/year, CI [0.09, 0.39], P = 0.003). We also observed some regional trends that the remyelinating response to bexarotene was linked with measures of biological age at baseline. For example, after adjustment for chronological age, remyelination of brainstem lesions assessed by magnetization transfer ratio was reduced by 0.06 pu for each year increase in BAMRI (CI [0.00, 0.13], P = 0.058) and 0.02 pu for each year increase in BABlood (CI [−0.01, 0.05], P = 0.17). This is, to the best of our knowledge, the first demonstration that MRI brain age can be therapeutically modulated by a drug in people with a neurological disorder. Overall, these findings highlight that beyond chronological age, biological age may also influence the potential for repair and should be considered when developing treatments for multiple sclerosis

Performance characteristics of an instrument-free point-of-care CD4 test (VISITECTVR CD4) for use in resource-limited settings

Objective: CD4þ T lymphocyte count remains the most common biomarker of immune status and disease progression in human immunodeficiency virus (HIV)-positive individuals. VISITECTVR CD4 is an instrument-free, low-cost point-of-care CD4 test with a cut-off of 350 CD4 cells/lL. This study aimed to evaluate VISITECTVR CD4 test’s diagnostic accuracy. Methods: Two hundred HIV-positive patients attending a tertiary HIV centre in South India were recruited. Patients provided venous blood for reference and VISITECTVR CD4 tests. An additional finger-prick blood sample was obtained for VISITECTVR CD4. VISITECTVR CD4’s diagnostic performance in identifying individuals with CD4 counts 350 cells/lL was assessed by calculating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) taking flow cytometry as the reference. Results: The overall agreement between VISITECTVR CD4 and flow cytometry was 89.5% using venous blood and 81.5% using finger-prick blood. VISITECTVR CD4 showed better performance using venous blood [sensitivity: 96.6% (95% confidence interval: 92.1%–98.9%), specificity: 70.9% (57.1%–82.4%), PPV: 89.7% (83.9%–94.0%) and NPV: 88.6% (75.4%–96.2%)] than using fingerprick blood [sensitivity: 84.8% (77.9%–90.2%), specificity: 72.7% (59.0%–83.9%), PPV: 89.1% (82.7%–93.8%) and NPV: 64.5% (51.3%–76.3%)]. Conclusion: VISITECTVR CD4 performed well using venous blood, demonstrating its potential utility in decentralization of CD4 testing services in resource-constrained settings

Changes in the Oligodendrocyte Progenitor Cell Proteome with Ageing.

Following central nervous system (CNS) demyelination, adult oligodendrocyte progenitor cells (OPCs) can differentiate into new myelin-forming oligodendrocytes in a regenerative process called remyelination. Although remyelination is very efficient in young adults, its efficiency declines progressively with ageing. Here we performed proteomic analysis of OPCs freshly isolated from the brains of neonate, young and aged female rats. Approximately 50% of the proteins are expressed at different levels in OPCs from neonates compared with their adult counterparts. The amount of myelin-associated proteins, and proteins associated with oxidative phosphorylation, inflammatory responses and actin cytoskeletal organization increased with age, whereas cholesterol-biosynthesis, transcription factors and cell cycle proteins decreased. Our experiments provide the first ageing OPC proteome, revealing the distinct features of OPCs at different ages. These studies provide new insights into why remyelination efficiency declines with ageing and potential roles for aged OPCs in other neurodegenerative diseases

The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination.

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination-the regeneration of myelin sheaths-also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.This work was supported by grants from UK Multiple Sclerosis Society, The British Trust for the Myelin Project, MedImmune, The Adelson Medical Research Foundation, Wellcome Trust, BBSRC, the Leverhulme Trust and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute. CEM was supported by grants from the Jean Shanks Foundation and the James Baird Fund, AGF was supported by an ECTRIMS fellowship and OBZ received a BIRAX fellowship

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease

Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation