Effect of extracellular polymeric compositions on in-situ sludge minimization performance of upgraded activated sludge treatment for industrial wastewater.

The sludge yield minimization from advanced biological treatment for industrial wastewater could be considered a poorly explored area, therefore, seeks serious attention of the scientific community. Up to best of the knowledge, the extracellular polymeric substances (EPS) profile underlying an upgraded activated sludge treatment (as MANODOX system) for real tannery wastewater has not been addressed in a desired manner. This study covers the elucidation of EPS degradation mechanism and floc morphology underlying MANODOX system for the treatment of real tannery influent. For this purpose, a modified heat extraction method was followed for the estimation of EPS fractions like protein (PN), polysaccharides (PS) and humic contents from the sludge. For the present investigation, the variation in floc characteristics including PN/PS ratio, sludge hydrophobicity, sludge volume index, and facultative microbiota at corresponding change in hydrodynamic sludge retention time (SRT) of 08-40 days was emphasized. The strict maintenance of adapted operational strategies including favoring range of SRT (24 days) for MANODOX implementation succeeded an outstanding in-situ sludge yield minimization lowered up to 0.39 gMLSS/gTCOD that attributed to three times lowered accumulation of PN and PS, comparably lower PN/PS ratio, higher salinity of the mixed liquid, weakened cell-to-cell attachment compared with a parallel run identical aerobic treatment. Here, the reason for improved hydrophobicity and corresponding decline in floc aggregation was attributed to change in sludge PN/PS ratio, carbon to nitrogen ratio of feed influent. The observations confirmed that the sludge yield minimization from MANODOX like systems could be effectively controlled by maintaining aforementioned operational tactics.

Defective survival of naive CD8+ T lymphocytes in the absence of the beta3 regulatory subunit of voltage-gated calcium channels.

The survival of T lymphocytes requires sustained, Ca(2+) influx-dependent gene expression. The molecular mechanism that governs sustained Ca(2+) influx in naive T lymphocytes is unknown. Here we report an essential role for the beta3 regulatory subunit of voltage-gated calcium (Ca(v)) channels in the maintenance of naive CD8(+) T cells. Deficiency in beta3 resulted in a profound survival defect of CD8(+) T cells. This defect correlated with depletion of the pore-forming subunit Ca(v)1.4 and attenuation of T cell antigen receptor (TCR)-mediated global Ca(2+) entry in CD8(+) T cells. Ca(v)1.4 and beta3 associated with T cell signaling machinery and Ca(v)1.4 localized in lipid rafts. Our data demonstrate a mechanism by which Ca(2+) entry is controlled by a Ca(v)1.4-beta3 channel complex in T cells.

Monocarboxylate transporter 1 in Schwann cells contributes to maintenance of sensory nerve myelination during aging.

Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1 f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/- , MCT1 f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, reduced mechanical sensitivity is evident in aged P0-Cre+/- , MCT1 f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein, and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the contribution of SC MCT1 to both SC metabolism and peripheral nerve maturation and aging.

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy.

The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.

Metabolic Connection of Inflammatory Pain: Pivotal Role of a Pyruvate Dehydrogenase Kinase-Pyruvate Dehydrogenase-Lactic Acid Axis.

Pyruvate dehydrogenase kinases (PDK1-4) are mitochondrial metabolic regulators that serve as decision makers via modulation of pyruvate dehydrogenase (PDH) activity to convert pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Metabolic dysregulation and inflammatory processes are two sides of the same coin in several pathophysiological conditions. The lactic acid surge associated with the metabolic shift has been implicated in diverse painful states. In this study, we investigated the role of PDK-PDH-lactic acid axis in the pathogenesis of chronic inflammatory pain. Deficiency of Pdk2 and/or Pdk4 in mice attenuated complete Freund's adjuvant (CFA)-induced pain hypersensitivities. Likewise, Pdk2/4 deficiency attenuated the localized lactic acid surge along with hallmarks of peripheral and central inflammation following intraplantar administration of CFA. In vitro studies supported the role of PDK2/4 as promoters of classical proinflammatory activation of macrophages. Moreover, the pharmacological inhibition of PDKs or lactic acid production diminished CFA-induced inflammation and pain hypersensitivities. Thus, a PDK-PDH-lactic acid axis seems to mediate inflammation-driven chronic pain, establishing a connection between metabolism and inflammatory pain. SIGNIFICANCE STATEMENT: The mitochondrial pyruvate dehydrogenase (PDH) kinases (PDKs) and their substrate PDH orchestrate the conversion of pyruvate either aerobically to acetyl-CoA or anaerobically to lactate. Lactate, the predominant end product of glycolysis, has recently been identified as a signaling molecule for neuron-glia interactions and neuronal plasticity. Pathological metabolic shift and subsequent lactic acid production are thought to play an important role in diverse painful states; however, their contribution to inflammation-driven pain is still to be comprehended. Here, we report that the PDK-PDH-lactic acid axis constitutes a key component of inflammatory pain pathogenesis. Our findings establish an unanticipated link between metabolism and inflammatory pain. This study unlocks a previously ill-explored research avenue for the metabolic control of inflammatory pain pathogenesis.

Pyruvate dehydrogenase kinase 2 and 4 gene deficiency attenuates nociceptive behaviors in a mouse model of acute inflammatory pain.

Pyruvate dehydrogenase (PDH) kinases (PDKs) 1-4, expressed in peripheral and central tissues, regulate the activity of the PDH complex (PDC). The PDC is an important mitochondrial gatekeeping enzyme that controls cellular metabolism. The role of PDKs in diverse neurological disorders, including neurometabolic aberrations and neurodegeneration, has been described. Implications for a role of PDKs in inflammation and neurometabolic coupling led us to investigate the effect of genetic ablation of PDK2/4 on nociception in a mouse model of acute inflammatory pain. Deficiency in Pdk2 and/or Pdk4 in mice led to attenuation of formalin-induced nociceptive behaviors (flinching, licking, biting, or lifting of the injected paw). Likewise, the pharmacological inhibition of PDKs substantially diminished the nociceptive responses in the second phase of the formalin test. Furthermore, formalin-provoked paw edema formation and mechanical and thermal hypersensitivities were significantly reduced in Pdk2/4-deficient mice. Formalin-driven neutrophil recruitment at the site of inflammation, spinal glial activation, and neuronal sensitization were substantially lessened in the second or late phase of the formalin test in Pdk2/4-deficient animals. Overall, our results suggest that PDK2/4 can be a potential target for the development of pharmacotherapy for the treatment of acute inflammatory pain. © 2016 Wiley Periodicals, Inc.

Lipocalin-2 in the Inflammatory Activation of Brain Astrocytes.

Lipocalin-2 (LCN2), a secretory protein, regulates diverse cellular processes such as cell death/survival, cell migration/invasion, cell differentiation, iron delivery, inflammation, insulin resistance, and tissue regeneration. Recently, we reported that LCN2 is secreted by brain astrocytes under inflammatory conditions and that it promotes apoptosis, morphological changes, and migration in astrocytes both in vitro and in vivo. Activated astrocytes release LCN2 not only to induce the morphological transformation associated with reactive astrocytosis, but also to promote their own death. Under inflammatory conditions, activated astrocytes also show functional dichotomy similar to the M1/M2 phenotypes of microglia and macrophages. LCN2 is thought to be a chemokine inducer and an autocrine promoter of the classical proinflammatory activation of astrocytes. This article summarizes the current knowledge regarding the role of astrocyte-derived LCN2 as a proinflammatory mediator in the central nervous system and discusses LCN2's role in neuroinflammatory disorders.

Proteome of brain glia: the molecular basis of diverse glial phenotypes.

Several different types of nonneuronal glial cells with diverse phenotypes are present in the CNS, and all have distinct indispensible functions. Although glial cells primarily provide neurons with metabolic and structural support in the healthy brain, they may switch phenotype from a "resting" to a "reactive" state in response to pathological insults. Furthermore, this reactive gliosis is an invariant feature of the pathogeneses of CNS maladies. The glial proteome serves as a signature of glial phenotype, and not only executes physiological functions, but also acts as a molecular mediator of the reactive glial phenotype. The glial proteome is also involved in intra- and intercellular communications as exemplified by glia-glia and neuron-glia interactions. The utilization of authoritative proteomic tools and the bioinformatic analyses have helped to profile the brain glial proteome and explore the molecular mechanisms of diverse glial phenotypes. Furthermore, technologic innovations have equipped the field of "glioproteomics" with refined tools for studies of the expression, interaction, and function of glial proteins in the healthy and in the diseased CNS. Glioproteomics is expected to contribute to the elucidation of the molecular mechanisms of CNS pathophysiology and to the discovery of biomarkers and theragnostic targets in CNS disorders.

Anti-serpin antibody-mediated regulation of proteases in autoimmune diabetes.

Secretion of anti-serpin B13 autoantibodies in young diabetes-prone nonobese diabetic mice is associated with reduced inflammation in pancreatic islets and a slower progression to autoimmune diabetes. Injection of these mice with a monoclonal antibody (mAb) against serpin B13 also leads to fewer inflammatory cells in the islets and more rapid recovery from recent-onset diabetes. The exact mechanism by which anti-serpin activity is protective remains unclear. We found that serpin B13 is expressed in the exocrine component of the mouse pancreas, including the ductal cells. We also found that anti-serpin B13 mAb blocked the inhibitory activity of serpin B13, thereby allowing partial preservation of the function of its target protease. Consistent with the hypothesis that anti-clade B serpin activity blocks the serpin from binding, exposure to exogenous anti-serpin B13 mAb or endogenous anti-serpin B13 autoantibodies resulted in cleavage of the surface molecules CD4 and CD19 in lymphocytes that accumulated in the pancreatic islets and pancreatic lymph nodes but not in the inguinal lymph nodes. This cleavage was inhibited by an E64 protease inhibitor. Consequently, T cells with the truncated form of CD4 secreted reduced levels of interferon-γ. We conclude that anti-serpin antibodies prevent serpin B13 from neutralizing proteases, thereby impairing leukocyte function and reducing the severity of autoimmune inflammation.

Role of lipocalin-2-chemokine axis in the development of neuropathic pain following peripheral nerve injury.

Lipocalin 2 (LCN2), which is also known as 24p3 and neutrophil gelatinase-associated lipocalin (NGAL), binds small, hydrophobic ligands and interacts with cell surface receptor 24p3R to regulate diverse cellular processes. In the present study, we examined the role of LCN2 in the pathogenesis of neuropathic pain using a mouse model of spared nerve injury (SNI). Lcn2 mRNA levels were significantly increased in the dorsal horn of the spinal cord after SNI, and LCN2 protein was mainly localized in neurons of the dorsal and ventral horns. LCN2 receptor 24p3R was expressed in spinal neurons and microglia after SNI. Lcn2-deficient mice exhibited significantly less mechanical pain hypersensitivity during the early phase after SNI, and an intrathecal injection of recombinant LCN2 protein elicited mechanical pain hypersensitivity in naive animals. Lcn2 deficiency, however, did not affect acute nociceptive pain. Lcn2-deficient mice showed significantly less microglial activation and proalgesic chemokine (CCL2 and CXCL1) production in the spinal cord after SNI than wild-type mice, and recombinant LCN2 protein induced the expression of these chemokines in cultured neurons. Furthermore, the expression of LCN2 and its receptor was detected in neutrophils and macrophages in the sciatic nerve following SNI, suggesting the potential role of peripheral LCN2 in neuropathic pain. Taken together, our results indicate that LCN2 plays a critical role in the development of pain hypersensitivity following peripheral nerve injury and suggest that LCN2 mediates neuropathic pain by inducing chemokine expression and subsequent microglial activation.

The secretome signature of reactive glial cells and its pathological implications.

Glial cells are non-neuronal components of the central nervous system (CNS). They are endowed with diverse functions and are provided with tools to detect their own activities and those of neighboring neurons. Glia and neurons are in continuous reciprocal communication under both physiological and neuropathological conditions, and glia secrete various guidance factors or proteinaceous signals that service vital neuronal-glial interactions in health and disease. Analysis and profiling of glial secretome, especially of microglia and astrocytes, have raised new expectations for the diagnosis and treatment of CNS disorders, and the availability of a catalog of glia-secreted proteins might provide an origin for further research on the complex extracellular signaling mediated by glial cells. Components of the glial secretome play important roles as mediators and modulators of brain structure and function during neuroprotection and neurodegeneration. Therapeutic hypothermia has been acclaimed an effective modulator of brain injury via its substantial effect on the protein expression profiles of glia. Furthermore, emerging proteomic tools and methodologies make feasible the documentation of the reactive glial secretome signature. This review focuses on reactive glial cells and the uniqueness of their secretome during diverse neuropathological conditions. This article is part of a Special Issue entitled: An Updated Secretome.

Serious Concern of Congenital Zika Syndrome (CZS) in India: A Narrative Review.

Congenital Zika syndrome (CZS) is a major concern in India and highlights the multifaceted challenges posed by the Zika virus (ZIKV). The alarming increase in CZS cases in India, a condition that has serious effects on both public health and newborns, has raised concerns. This review highlights the importance of raising concern and awareness and taking preventive measures by studying the epidemiology, clinical symptoms, and potential long-term consequences of CZS. The review also contributes to worldwide research and information sharing to improve the understanding and prevention of CZS. As India deals with the changing nature of CZS, this thorough review is an important tool for policymakers, health workers, and researchers to understand what is happening now, plan for what to do in the future, and work together as a team, using medical knowledge, community involvement, and study projects to protect newborns' health and reduce the public health impact of these syndromes.

Influence of Hepatitis C virus genotype and other factors on the viral load.

Anti-HCV reactive subjects were selected and relevant data was collected. Viral load and genotype were determined for all patients and were divided into low (<800,000 IU/mL) and high viral load (>800,000 IU/mL). Correlation of viral load with parameters like age, gender, risk factors and genotype etc. was determined by binomial regression. Higher viral load was noted with genotype 4, males and high risk groups like People Who Inject Drugs (PWIDs), blood transfusion before routine testing or frequent transfusion, Intravenous drug therapy and MTP by unregistered medical practitioners (P ≤ 0.5). Prevention and treatment strategies for HCV should be tailored around these areas.

Glia-based biomarkers and their functional role in the CNS.

Glial cells, a close partner to neurons, are able to communicate with each other and with neurons through secreted proteins and other molecules. Secreted proteins in the extracellular environment probably play a direct role in the control and regulation of numerous biological and disease processes in the nervous system. Provision of precise diagnosis and prognosis to patients with a neurological disorder is problematic. Glial activation is a hallmark of every type of injury to the nervous system. In these circumstances, it is the glial biomarker whose development and implementation can be the most suitable approach to assessment of neuroinflammation and neurotoxicity. Here, the importance of glial secreted proteins as diagnostic/prognostic biomarkers and their functional contribution to regulation of neuroinflammation are reviewed. Evidence for the use of glia-based biomarkers for improvement of diagnostic and prognostic accuracy is also summarized and recommendations for future glia-based biomarker research are provided.

Adoptive cell transfer of macrophages following peripheral nerve injury in mice.

Macrophages are key innate immune cells involved in multiple biological processes, including peripheral nerve regeneration. Here, we describe a protocol for the adoptive cell transfer of bone-marrow-derived macrophages (BMDMs) following sciatic nerve crush injury (SNCI). This procedure involves isolating BMDMs from a donor mouse, potentially manipulating them ex vivo, and reintroducing them into an animal following SNCI. Preclinical studies show that BMDMs can infiltrate injured nerves and impact functional recovery, potentially providing a novel therapy for nerve injuries. For complete details on the use and execution of this protocol, please refer to Jha et al.1.

Impact of KOH Activation on Rice Husk Derived Porous Activated Carbon for Carbon Capture at Flue Gas alike Temperatures with High CO2/N2 Selectivity.

Metal-free porous activated carbon is an effective alternative to capture CO2 due to its high surface area and textural advantages. In this regard, the present research work explores a suitable method for producing activated porous carbon with a high specific surface area through a two-step reaction involving rice husk and KOH at 600 °C for 1 h to capture CO2. By varying the ratio of rice husk biomass to KOH, the texture and specific surface area of the activated porous carbon has been altered. A high surface area of ∼755 m2/g and a micropore volume of 0.243 cm3/g have been observed in the porous carbon produced with a KOH/biomass weight ratio of 3 (PAC2). Nitrogen contents in PAC1 and PAC2 were approximately 2.27 and 2.71 atom %, respectively. When compared with other materials, PAC2 has the highest CO2 adsorption capability, reaching up to 3.13 mmol/g at 0 °C and 1.55 mmol/g at 50 °C. The isosteric heat of adsorption confirms the presence of both physisorption and chemisorption. The materials turn out to be highly CO2/N2 selective, with the highest selectivity of 131, proving that the samples are potential materials for capturing CO2 from flue gases. These findings unequivocally show that porous activated carbon can be used to make CO2 adsorption efficient, inexpensive, and, more importantly, extremely effective.

Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group, randomised controlled trial.

BACKGROUND: Maintenance antipsychotic medication is recommended for people with schizophrenia or recurrent psychosis, but the adverse effects are burdensome, and evidence on long-term outcomes is sparse. We aimed to assess the benefits and harms of a gradual process of antipsychotic reduction compared with maintenance treatment. Our hypothesis was that antipsychotic reduction would improve social functioning with a short-term increase in relapse. METHODS: RADAR was an open, parallel-group, randomised trial done in 19 National Health Service Trusts in England. Participants were aged 18 years and older, had a diagnosis of recurrent, non-affective psychotic disorder, and were prescribed an antipsychotic. Exclusion criteria included people who had a mental health crisis or hospital admission in the past month, were considered to pose a serious risk to themselves or others by a treating clinician, or were mandated to take antipsychotic medication under the Mental Health Act. Through an independent, internet-based system, participants were randomly assigned (1:1) to gradual, flexible antipsychotic reduction, overseen by treating clinicians, or to maintenance. Participants and clinicians were aware of treatment allocations, but assessors were masked to them. Follow-up was for 2 years. Social functioning, assessed by the Social Functioning Scale, was the primary outcome. The principal secondary outcome was severe relapse, defined as requiring admission to hospital. Analysis was done blind to group identity using intention-to-treat data. The trial is completed and has been registered with ISRCTN registry (ISRCTN90298520) and with ClinicalTrials.gov (NCT03559426). FINDINGS: 4157 people were screened, of whom 253 were randomly allocated, including 168 (66%) men, 82 (32%) women, and 3 (1%) transgender people, with a mean age of 46 years (SD 12, range 22-79). 171 (67%) participants were White, 52 (21%) were Black, 16 (6%) were Asian, and 12 (5%) were of other ethnicity. The median dose reduction at any point during the trial was 67% in the reduction group and zero in the maintenance group; at 24 months it was 33% versus zero. At the 24-month follow-up, we assessed 90 of 126 people assigned to the antipsychotic dose reduction group and 94 of 127 assigned to the maintenance group, finding no difference in the Social Functioning Scale (ß 0·19, 95% CI -1·94 to 2·33; p=0·86). There were 93 serious adverse events in the reduction group affecting 49 individuals, mainly comprising admission for a mental health relapse, and 64 in the maintenance group, relating to 29 individuals. INTERPRETATION: At 2-year follow-up, a gradual, supported process of antipsychotic dose reduction had no effect on social functioning. Our data can help to inform decisions about the use of long-term antipsychotic medication. FUNDING: National Institute for Health Research.

Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders.

Metabolism is involved directly or indirectly in all processes conducted in living cells. The brain, popularly viewed as a neuronal-glial complex, gets most of its energy from the oxygen-dependent metabolism of glucose, and the mitochondrial pyruvate dehydrogenase complex (PDC) plays a key regulatory role during the oxidation of glucose. Pyruvate dehydrogenase kinase (also called PDC kinase or PDK) is a kinase that regulates glucose metabolism by switching off PDC. Four isoforms of PDKs with tissue specific activities have been identified. The metabolisms of neurons and glial cells, especially, those of astroglial cells, are interrelated, and these cells function in an integrated fashion. The energetic coupling between neuronal and astroglial cells is essential to meet the energy requirements of the brain in an efficient way. Accumulating evidence suggests that alterations in the PDKs and/or neuron-astroglia metabolic interactions are associated with the development of several neurological disorders. Here, the authors review the results of recent research efforts that have shed light on the functions of PDKs in the nervous system, particularly on neuron-glia metabolic interactions and neuro-metabolic disorders.

Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis.

Cytolytic CD8(+) T cells (CTLs) kill virally infected cells, tumor cells, or other potentially autoreactive T cells in a calcium-dependent manner. To date, the molecular mechanism that leads to calcium intake during CTL differentiation and function has remained unresolved. We demonstrate that desmoyokin (AHNAK1) is expressed in mature CTLs, but not in naive CD8(+) T cells, and is critical for calcium entry required for their proper function during immune response. We show that mature AHNAK1-deficient CTLs exhibit reduced Ca(v)1.1 alpha1 subunit expression (also referred to as L-type calcium channels or alpha1S pore-forming subunits), which recently were suggested to play a role in calcium entry into CD4(+) T cells. AHNAK1-deficient CTLs show marked reduction in granzyme-B production, cytolytic activity, and IFN-gamma secretion after T cell receptor stimulation. Our results demonstrate an AHNAK1-dependent mechanism controlling calcium entry during CTL effector function.

Matching ICD-11 personality status to clinical management in a community team-The Boston (UK) Personality Project: Study protocol.

Epidemiological studies show 30% to 50% of all patients in community mental health teams have personality disorders. These are normally comorbid with other psychiatric disorders, often as Galenic syndromes, and are seldom identified. In the Boston (UK) Personality Project all patients under a community health service in Boston in Lincolnshire will be asked to agree to have their personality status assessed using scales recording the new ICD-11 classification, together with clinical ratings, social function and satisfaction. A control group of 100 patients from an adjacent service of similar demographics (Spalding) will also have similar ratings but no personality assessments. Changes in clinical status, social function and service satisfaction will be made after 6 and 12 months in both groups. The patients in the Boston group will be offered matched interventions using a stepped care approach for both the severity of disorder and its domain structure. These interventions will include shorter versions of existing psychological treatments, environmental therapies including nidotherapy, adaptive and acceptance models, drug reduction and social prescribing. Full costs of psychiatric care will be measured in both groups. The main hypothesis is that greater awareness of personality function will lead to better clinical outcomes and satisfaction.