A Recovery-Oriented Intervention for People With Psychosis: A Pilot Randomized Controlled Trial.

OBJECTIVE: This pilot randomized controlled trial evaluated the effectiveness of critical time intervention-task shifting (CTI-TS) for people with psychosis in Santiago, Chile, and Rio de Janeiro. CTI-TS is a 9-month intervention involving peer support workers and is designed to maintain treatment effects up to 18 months. METHODS: A total of 110 people with psychosis were recruited when they enrolled in community mental health clinics (Santiago, N=60; Rio de Janeiro, N=50). Participants within each city were randomly assigned to either CTI-TS or usual care for 9 months. Primary outcomes were quality of life, measured with the World Health Organization Quality of Life Assessment-Brief Version (WHOQOL-BREF), and unmet needs, measured with the Camberwell Assessment of Need (CAN), at 18-month follow-up. Results were analyzed according to intention-to-treat guidelines. Generalized estimating equations, with observations clustered within cities, and multiple imputation for missing data were used. RESULTS: At 18 months, both groups showed improved primary outcomes. In both unadjusted and fully adjusted analyses, no significant differences between CTI-TS and usual care (WHOQOL-BREF question on quality of life and CAN mean number of unmet needs) were found. CONCLUSIONS: Three factors might explain the lack of difference between CTI-TS and usual care: first-contact enrollment precluded rapport prior to randomization, a minority of patients were uncomfortable with peers being on the treatment team, and primary outcome measures may not have been sensitive enough to capture the effects of a recovery-oriented intervention. The results have implications for the design of transitional services for people with psychosis, especially in Latin America.

Crisis Response as a Human Rights Flashpoint: Critical Elements of Community Support for Individuals Experiencing Significant Emotional Distress.

This paper proposes a set of nine critical elements underpinned by human rights principles to support individuals experiencing a serious crisis related to mental health problems or psychosocial disabilities. These elements are distilled from a range of viable alternatives to traditional community mental health approaches and are linked to a normative human rights framework. We argue that crisis response is one of the areas of mental health care where there is a heightened risk that the rights of service recipients may be infringed. We further make the case that the nine critical elements found in advanced mental health care models should be used as building blocks for designing services and systems that promote effective rights-based care and supports.

Open Dialogue as a Human Rights-Aligned Approach.

Throughout the last 20 years, the human rights perspective has increasingly developed into a paradigm against which to appraise and evaluate mental health care. This article investigates to what extent the Finnish open dialogue (OD) approach both aligns with human rights and may be qualified to strengthen compliance with human rights perspectives in global mental health care. Being a conceptual paper, the structural and therapeutic principles of OD are theoretically discussed against the background of human rights, as framed by the Universal Declaration of Human Rights, the UN Convention on the Rights of People with Disabilities, and the two recent annual reports of the Human Rights Council. It is shown that OD aligns well with discourses on human rights, being a largely non-institutional and non-medicalizing approach that both depends on and fosters local and context-bound forms of knowledge and practice. Its fundamental network perspective facilitates a contextual and relational understanding of mental well-being, as postulated by contemporary human rights approaches. OD opens the space for anyone to speak (out), for mutual respect and equality, for autonomy, and to address power differentials, making it well suited to preventing coercion and other forms of human rights violation. It is concluded that OD can be understood as a human rights-aligned approach.

Implementing the protocol of a pilot randomized controlled trial for the recovery-oriented intervention to people with psychoses in two Latin American cities.

Several Latin American countries have made remarkable strides towards offering community mental health care for people with psychoses. Nonetheless, mental health clinics generally have a very limited outreach in the community, tending to have weaker links to primary health care; rarely engaging patients in providing care; and usually not providing recovery-oriented services. This paper describes a pilot randomized controlled trial (RCT) of Critical Time Intervention-Task Shifting (CTI-TS) aimed at addressing such limitations. The pilot RCT was conducted in Santiago (Chile) and Rio de Janeiro (Brazil). We included 110 people with psychosis in the study, who were recruited at the time of entry into community mental health clinics. Trial participants were randomly divided into CTI-TS intervention and usual care. Those allocated to the intervention group received usual care and, in addition, CTI-TS services over a 9-month period. Primary outcomes include quality of life (WHO Quality of Life Scale - Brief Version) and unmet needs (Camberwell Assessment of Needs) at the 18-month follow-up. Primary outcomes at 18 months will be analyzed by Generalized Estimating Equations (GEE), with observations clustered within sites. We will use three-level multilevel models to examine time trends on the primary outcomes. Similar procedures will be used for analyzing secondary outcomes. Our hope is that this trial provides a foundation for planning a large-scale multi-site RCT to establish the efficacy of recovery-oriented interventions such as CTI-TS in Latin America.

Implementing the protocol of a pilot randomized controlled trial for the recovery-oriented intervention to people with psychoses in two Latin American cities / Implementação de um protocolo para um estudo piloto randomizado e controlado sobre uma intervenção voltada para a recuperação em pessoas com psicoses em duas cidades latino-americanas / Implementando un protocolo para una prueba piloto controlada aleatorizada en una intervención orientada a la recuperación de personas con psicosis en dos ciudades latinoamericanas

Several Latin American countries have made remarkable strides towards offering community mental health care for people with psychoses. Nonetheless, mental health clinics generally have a very limited outreach in the community, tending to have weaker links to primary health care; rarely engaging patients in providing care; and usually not providing recovery-oriented services. This paper describes a pilot randomized controlled trial (RCT) of Critical Time Intervention-Task Shifting (CTI-TS) aimed at addressing such limitations. The pilot RCT was conducted in Santiago (Chile) and Rio de Janeiro (Brazil). We included 110 people with psychosis in the study, who were recruited at the time of entry into community mental health clinics. Trial participants were randomly divided into CTI-TS intervention and usual care. Those allocated to the intervention group received usual care and, in addition, CTI-TS services over a 9-month period. Primary outcomes include quality of life (WHO Quality of Life Scale - Brief Version) and unmet needs (Camberwell Assessment of Needs) at the 18-month follow-up. Primary outcomes at 18 months will be analyzed by Generalized Estimating Equations (GEE), with observations clustered within sites. We will use three-level multilevel models to examine time trends on the primary outcomes. Similar procedures will be used for analyzing secondary outcomes. Our hope is that this trial provides a foundation for planning a large-scale multi-site RCT to establish the efficacy of recovery-oriented interventions such as CTI-TS in Latin America.

Diversos países latino-americanos já alcançaram avanços notáveis na oferta de assistência em saúde mental para pessoas com psicoses. No entanto, as clínicas de saúde mental geralmente realizam atividades de extensão muito limitadas dentro das comunidades, tendem a ter vínculos fracos com a assistência primária, raramente envolvem os próprios pacientes nos cuidados e poucas vezes prestam serviços orientados para a recuperação. O artigo descreve um estudo piloto randomizado e controlado sobre a Critical Time Intervention-Task Shifting (CTI-TS), que teve como objetivo analisar essas limitações. O estudo piloto foi realizado em Santiago (Chile) e no Rio de Janeiro (Brasil). Teve como meta a inclusão de 110 pessoas com psicose, recrutadas no momento da entrada em clínicas comunitárias de saúde mental. Os participantes foram randomizados para o CTI-TS ou para os cuidados usuais. Aqueles alocados ao grupo da intervenção receberam os cuidados usuais e os serviços de CTI-TS ao longo de 9 meses. Os desfechos primários incluíram a qualidade de vida (WHO Quality of Life Scale - Brief Version) e as necessidades não atendidas (Camberwell Assessment of Needs) no acompanhamento aos 18 meses. Os desfechos primários aos 18 meses serão analisados com a técnica de Equações de Estimação Generalizadas (GEE), com as observações agrupadas dentro dos locais do estudo. Serão utilizados modelos em três níveis para examinar as tendências temporais nos desfechos primários. Procedimentos semelhantes serão utilizados para analisar os resultados secundários. Espera-se que o estudo forneça uma base para planejar um estudo randomizado e controlado em grande escala e em múltiplos locais para estabelecer a eficácia da intervenção orientada para a recuperação, a exemplo da CTI-TS, na América Latina.

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Dynamic Co-evolution of Host and Pathogen: HCMV Downregulates the Prevalent Allele MICA∗008 to Escape Elimination by NK Cells.

Natural killer (NK) cells mediate innate immune responses against hazardous cells and are particularly important for the control of human cytomegalovirus (HCMV). NKG2D is a key NK activating receptor that recognizes a family of stress-induced ligands, including MICA, MICB, and ULBP1-6. Notably, most of these ligands are targeted by HCMV proteins and a miRNA to prevent the killing of infected cells by NK cells. A particular highly prevalent MICA allele, MICA∗008, is considered to be an HCMV-resistant "escape variant" that confers advantage to human NK cells in recognizing infected cells. However, here we show that HCMV uses its viral glycoprotein US9 to specifically target MICA∗008 and thus escapes NKG2D attack. The finding that HCMV evolved a protein dedicated to countering a single host allele illustrates the dynamic co-evolution of host and pathogen.

High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant.

BACKGROUND: A noninvasive biomarker that could accurately diagnose acute rejection (AR) in heart transplant recipients could obviate the need for surveillance endomyocardial biopsies. We assessed the performance metrics of a novel high-sensitivity cardiac troponin I (cTnI) assay for this purpose. METHODS AND RESULTS: Stored serum samples were retrospectively matched to endomyocardial biopsies in 98 cardiac transplant recipients, who survived ≥3 months after transplant. AR was defined as International Society for Heart and Lung Transplantation grade 2R or higher cellular rejection, acellular rejection, or allograft dysfunction of uncertain pathogenesis, leading to treatment for presumed rejection. cTnI was measured with a high-sensitivity assay (Abbott Diagnostics, Abbott Park, IL). Cross-sectional analyses determined the association of cTnI concentrations with rejection and International Society for Heart and Lung Transplantation grade and the performance metrics of cTnI for the detection of AR. Among 98 subjects, 37% had ≥1 rejection episode. cTnI was measured in 418 serum samples, including 35 paired to a rejection episode. cTnI concentrations were significantly higher in rejection versus nonrejection samples (median, 57.1 versus 10.2 ng/L; P<0.0001) and increased in a graded manner with higher biopsy scores (P(trend)<0.0001). The c-statistic to discriminate AR was 0.82 (95% confidence interval, 0.76-0.88). Using a cut point of 15 ng/L, sensitivity was 94%, specificity 60%, positive predictive value 18%, and negative predictive value 99%. CONCLUSIONS: A high-sensitivity cTnI assay seems useful to rule out AR in cardiac transplant recipients. If validated in prospective studies, a strategy of serial monitoring with a high-sensitivity cTnI assay may offer a low-cost noninvasive strategy for rejection surveillance.

Profiling antibodies to class II HLA in transplant patient sera.

Immunizing events including pregnancy, transfusions, and transplantation promote strong alloantibody responses to HLA. Such alloantibodies to HLA preclude organ transplantation, foster hyperacute rejection, and contribute to chronic transplant failure. Diagnostic antibody-screening assays detect alloreactive antibodies, yet key attributes including antibody concentration and isotype remain largely unexplored. The goal here was to provide a detailed profile of allogeneic antibodies to class II HLA. Methodologically, alloantibodies were purified from sensitized patient sera using an HLA-DR11 immunoaffinity column and subsequently categorized. Antibodies to DR11 were found to fix complement, exist at a median serum concentration of 2.3µg/mL, consist of all isotypes, and isotypes IgG2, IgM, and IgE were elevated. Because multimeric isotypes can confound diagnostic determinations of antibody concentration, IgM and IgA isotypes were removed and DR11-IgG tested alone. Despite removal of multimeric isotypes, patient-to-patient antibody concentrations did not correlate with MFI values. In conclusion, allogeneic antibody responses to DR11 are comprised of all antibody isotypes at differing proportions, these combined isotypes fix complement at nominal serum concentrations, and enhancements other than the removal of IgM and IgA multimeric isotypes may be required if MFI is to be used as a means of determining anti-HLA serum antibody concentrations in diagnostic clinical assays.

Identification of endothelial cell surface antigens encoded by genes other than HLA. A combined immunoprecipitation and proteomic approach for the identification of antigens recognized by antibodies against endothelial cells in transplant recipients.

It has been known for some time that transplant recipients may have antibodies to endothelial cells which are not detected on lymphocytes. However, little progress has been made in the analysis of these endothelial antigens. In the present experiments we have attempted to characterize endothelial cell surface antigens to which antibodies were produced during graft rejection. We have used a panel of endothelial cells from umbilical cord veins and found that antibodies with a polymorphic pattern in the panel appeared to correlate with transplant failure of kidney allografts and with the development of transplant-related coronary artery disease (TCAD) in heart transplant recipients. Among 39 patients with kidney allografts, 21 were negative for antibodies to endothelial cells and did well and 18 were positive and had frequent transplant loss (p=0.001). In 18 patients with TCAD and 20 patients of a comparator group without TCAD, association of coronary disease with endothelial cell antibodies was observed (p<0.02). To characterize the endothelial antigens responsible for these serologic reactions we performed immunoprecipitation of reactive antibodies with the corresponding endothelial cell surface antigens, followed by protein identification of the target antigens. Nine proteins were identified in these experiments, 5 were non-polymorphic and appeared to represent autoantigens. Four of the isolated proteins appeared to be polymorphic. They were the Human Major Histocompatibility Complex class I chain-related gene A (MICA), already known to be associated with antibody production and graft failure, human keratin 1, a protein known to be polymorphic and expressed on the surface of endothelial cells, eukaryotic translation initiation factor (EIF) 2A and ErbB3-binding protein 1. The possible role of keratin 1 and the other antigens in allograft rejection requires further investigation.

Alleles of keratin 1 in families and populations.

Keratin 1 is found in the upper layers of the epidermis, on the surface of endothelial cells and in the membrane of the neuroblastoma NMB7. It is important for the structural integrity of the skin, has been found to regulate the activity of kinases, such as protein kinase C (PKC) and SRC, to participate in complement activation by the lectin pathway and to be involved in fibrinolysis, angiogenesis and the response to oxidative stress. Studies of the polymorphisms of the Keratin 1 (KRT1) gene have been driven mostly by interest in its role in skin diseases. However, much of the KRT1 variation occurs in normal populations and is not associated with dermal pathology. In the present experiments, we have investigated the polymorphism of KRT1 genes by nucleotide sequencing in normal families and normal populations of European, African, Hispanic and Asian background. The frequencies of the KRT1 alleles were strikingly different in the four ethnic groups and most of the mutations resulted in amino acid substitutions, with only 3 out of 19 being synonymous. Analysis of selective neutrality by the Ewens-Watterson and Tajima D statistics showed that KRT1 allele homozygosity was decreased in three of the populations suggesting that KRT1 genes may be under the influence of balancing selection. It is possible that the role of KRT1 as a receptor, rather than its structural function in the epidermis, is what drives the selective forces that are apparent in the inheritance of this gene.

[Peer specialist: origins, pitfalls and worldwide dissemination]. / Pares especializados: orígenes, resultados, dificultades y diseminación a nivel mundial.

This article reviews the origins, outcomes and implementation issues pertaining to the hiring of former psychiatric patients into paid Peer Specialist positions within mental health services. The term Peer Specialists, unlike various other job titles used for ex-psychiatric patients working in the mental health field, stands out as a unique qualifier that emphasizes the special knowledge such workers have acquired from experiencing serious personal crises and being involved in mental health services. The cautiously positive results of early studies are supplemented by replications of various quality and results. Further work has revealed a number of problematic issues, which will also be discussed here.

Pares especializados: orígenes, resultados, dificultades y diseminación a nivel mundial / [Peer specialist: origins, pitfalls and worldwide dissemination].

This article reviews the origins, outcomes and implementation issues pertaining to the hiring of former psychiatric patients into paid Peer Specialist positions within mental health services. The term Peer Specialists, unlike various other job titles used for ex-psychiatric patients working in the mental health field, stands out as a unique qualifier that emphasizes the special knowledge such workers have acquired from experiencing serious personal crises and being involved in mental health services. The cautiously positive results of early studies are supplemented by replications of various quality and results. Further work has revealed a number of problematic issues, which will also be discussed here.

Pares especializados: orígenes, resultados, dificultades y diseminación a nivel mundial. / [Peer specialist: origins, pitfalls and worldwide dissemination].

This article reviews the origins, outcomes and implementation issues pertaining to the hiring of former psychiatric patients into paid Peer Specialist positions within mental health services. The term Peer Specialists, unlike various other job titles used for ex-psychiatric patients working in the mental health field, stands out as a unique qualifier that emphasizes the special knowledge such workers have acquired from experiencing serious personal crises and being involved in mental health services. The cautiously positive results of early studies are supplemented by replications of various quality and results. Further work has revealed a number of problematic issues, which will also be discussed here.

High resolution MICA genotyping by sequence-based typing (SBT).

We have developed a MICA typing method based on polymerase chain reaction (PCR) sequence-based typing and a computer program that determines the polymorphisms and distinguishes the GCT repeats in exon 5. One PCR amplification was performed to obtain templates of 2.2 kb, including exons 2, 3, 4, and 5 of MICA to be sequenced with two forward and two reverse primers. Overlay of nucleotide sequencing signals resulting from presence of different GCT repeats in exon 5 from two different MICA alleles can be identified by a computer program that analyses the combined signal string containing the 35 bases.

Screening for antibodies against MICA by Luminex flow cytometry.

Antibodies against MICA have been found in organ transplant recipients and were found to be associated with decreased survival of kidney allografts. The MICA antibody screening assay is a Luminex-based solid phase immunoassay designed to detect IgG antibodies binding to beads pre-coated with recombinant preparations of MICA alleles. These beads coated with soluble MICA recombinant proteins including 11 common alleles have been produced in our laboratory and similar preparations have been available from commercial sources. Here, we describe the procedure of MICA antibody screening with a prepared kit, in which all the reagents were optimized and standardized. We also review how to document the quality of single MICA antigen beads using MICA-specific monoclonal antibodies, as well as quality control of the procedure and data analysis.

Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations.

The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.