Clinical and epidemiological descriptions from trichinellosis outbreaks in Bulgaria.

Bulgaria is one of European countries where trichinellosis continues to be regularly diagnosed and registered. The clinical and epidemiological features of 72 cases of trichinellosis associated with five outbreaks caused by Trichinella spiralis and Trichinella britovi between 2009 and 2011, are described. At hospital admission, patients were often initially treated with antibiotics, without any improvement. A range of signs and symptoms were recorded, including: myalgia, elevated temperature, arthralgia, difficulty with movement, facial oedema, conjunctival hyperaemia, ocular haemorrhages, diarrhoea, skin rash, headache, and fatigue. Due to the variable clinical course of the disease, the diagnostic process for trichinellosis is often complex and difficult. This means the diagnosis may be established late for an appropriate treatment, potentially leading to a severe course of the disease with complications. Laboratory abnormalities were expressed by marked eosinophilia (97.2%), leucocytosis (70.8%), elevated serum creatine phosphokinase levels (82%), and antibody-positive results by ELISA and indirect hemagglutination. Patients were treated with albendazole (Zentel) 10 mg/kg for 7-10 days. In two outbreaks, the aetiological agent was T. spiralis, in one outbreak T. britovi, and an unknown Trichinella species in the fourth outbreak. The sources of infection were domestic pigs, probably fed with scraps and offal of wild game. In one outbreak, T. spiralis was also detected in brown rats trapped close to where the pig had been raised in the backyard. These epidemiological factors are relevant in considering implementation of targeted control programmes.

DNA bipedal motor walking dynamics: an experimental and theoretical study of the dependency on step size.

We present a detailed coarse-grained computer simulation and single molecule fluorescence study of the walking dynamics and mechanism of a DNA bipedal motor striding on a DNA origami. In particular, we study the dependency of the walking efficiency and stepping kinetics on step size. The simulations accurately capture and explain three different experimental observations. These include a description of the maximum possible step size, a decrease in the walking efficiency over short distances and a dependency of the efficiency on the walking direction with respect to the origami track. The former two observations were not expected and are non-trivial. Based on this study, we suggest three design modifications to improve future DNA walkers. Our study demonstrates the ability of the oxDNA model to resolve the dynamics of complex DNA machines, and its usefulness as an engineering tool for the design of DNA machines that operate in the three spatial dimensions.

Study of DNA Origami Dimerization and Dimer Dissociation Dynamics and of the Factors that Limit Dimerization.

Organizing DNA origami building blocks into higher order structures is essential for fabrication of large structurally and functionally diverse devices and molecular machines. Unfortunately, the yields of origami building block attachment reactions are typically not sufficient to allow programed assembly of DNA devices made from more than a few origami building blocks. To investigate possible reasons for these low yields, a detailed single-molecule fluorescence study of the dynamics of rectangular origami dimerization and origami dimer dissociation reactions is conducted. Reactions kinetics and yields are investigated at different origami and ion concentrations, for different ion types, for different lengths of bridging strands, and for the "sticky end" and "weaving welding" attachment techniques. Dimerization yields are never higher than 86%, which is typical for such systems. Analysis of the dynamic data shows that the low yield cannot be explained by thermodynamic instability or structural imperfections of the origami constructs. Atomic force microscopy and gel electrophoresis evidence reveal self-dimerization of the origami monomers, likely via blunt-end interactions made possible by the presence of bridging strands. It is suggested that this mechanism is the major factor that inhibits correct dimerization and means to overcome it are discussed.

Nucleosome Core Particle Disassembly and Assembly Kinetics Studied Using Single-Molecule Fluorescence.

The stability of the nucleosome core particle (NCP) is believed to play a major role in regulation of gene expression. To understand the mechanisms that influence NCP stability, we studied stability and dissociation and association kinetics under different histone protein (NCP) and NaCl concentrations using single-pair Förster resonance energy transfer and alternating laser excitation techniques. The method enables distinction between folded, unfolded, and intermediate NCP states and enables measurements at picomolar to nanomolar NCP concentrations where dissociation and association reactions can be directly observed. We reproduced the previously observed nonmonotonic dependence of NCP stability on NaCl concentration, and we suggest that this rather unexpected behavior is a result of interplay between repulsive and attractive forces within positively charged histones and between the histones and the negatively charged DNA. Higher NaCl concentrations decrease the attractive force between the histone proteins and the DNA but also stabilize H2A/H2B histone dimers, and possibly (H3/H4)2 tetramers. An intermediate state in which one DNA arm is unwrapped, previously observed at high NaCl concentrations, is also explained by this salt-induced stabilization. The strong dependence of NCP stability on ion and histone concentrations, and possibly on other charged macromolecules, may play a role in chromosomal morphology.

A bipedal DNA motor that travels back and forth between two DNA origami tiles.

In this work, the successful operation of a dynamic DNA device constructed from two DNA origami building blocks is reported. The device includes a bipedal walker that strides back and forth between the two origami tiles. Two different DNA origami tiles are first prepared separately; they are then joined together in a controlled manner by a set of DNA strands to form a stable track in high yield as confirmed by single-molecule fluorescence (SMF). Second, a bipedal DNA motor, initially attached to one of the two origami units and operated by sequential interaction with "fuel" and "antifuel" DNA strands, moves from one origami tile to another and then back again. The operational yield, measured by SMF, was similar to that of a motor operating on a similar track embedded in a single origami tile, confirming that the transfer across the junction from one tile to the other does not result in dissociation that is any more than that of steps on a single tile. These results demonstrate that moving parts can reliably travel from one origami unit to another, and it demonstrates the feasibility of dynamic DNA molecular machines that are made of more than a single origami building block. This study is a step toward the development of motors that can stride over micrometer distances.

Developing DNA nanotechnology using single-molecule fluorescence.

CONSPECTUS: An important effort in the DNA nanotechnology field is focused on the rational design and manufacture of molecular structures and dynamic devices made of DNA. As is the case for other technologies that deal with manipulation of matter, rational development requires high quality and informative feedback on the building blocks and final products. For DNA nanotechnology such feedback is typically provided by gel electrophoresis, atomic force microscopy (AFM), and transmission electron microscopy (TEM). These analytical tools provide excellent structural information; however, usually they do not provide high-resolution dynamic information. For the development of DNA-made dynamic devices such as machines, motors, robots, and computers this constitutes a major problem. Bulk-fluorescence techniques are capable of providing dynamic information, but because only ensemble averaged information is obtained, the technique may not adequately describe the dynamics in the context of complex DNA devices. The single-molecule fluorescence (SMF) technique offers a unique combination of capabilities that make it an excellent tool for guiding the development of DNA-made devices. The technique has been increasingly used in DNA nanotechnology, especially for the analysis of structure, dynamics, integrity, and operation of DNA-made devices; however, its capabilities are not yet sufficiently familiar to the community. The purpose of this Account is to demonstrate how different SMF tools can be utilized for the development of DNA devices and for structural dynamic investigation of biomolecules in general and DNA molecules in particular. Single-molecule diffusion-based Förster resonance energy transfer and alternating laser excitation (sm-FRET/ALEX) and immobilization-based total internal reflection fluorescence (TIRF) techniques are briefly described and demonstrated. To illustrate the many applications of SMF to DNA nanotechnology, examples of SMF studies of DNA hairpins and Holliday junctions and of the interactions of DNA strands with DNA origami and origami-related devices such as a DNA bipedal motor are provided. These examples demonstrate how SMF can be utilized for measurement of distances and conformational distributions and equilibrium and nonequilibrium kinetics, to monitor structural integrity and operation of DNA devices, and for isolation and investigation of minor subpopulations including malfunctioning and nonreactive devices. Utilization of a flow-cell to achieve measurements of dynamics with increased time resolution and for convenient and efficient operation of DNA devices is discussed briefly. We conclude by summarizing the various benefits provided by SMF for the development of DNA nanotechnology and suggest that the method can significantly assist in the design and manufacture and evaluation of operation of DNA devices.

Alcohol abuse in developed and developing countries in the World Mental Health Surveys: Socially defined consequences or psychiatric disorder?

BACKGROUND: Previous single country research has raised concerns that: (1) the DSM-IV diagnosis of alcohol abuse (AA) is met primarily through the hazardous use criterion related to drinking and driving and (2) that the hazardous use and social consequences AA criteria primarily reflect varying socioeconomic and cultural factors rather than psychiatric disorder. METHODS: Using representative cross-national data from the 21 countries in the World Mental Health surveys, adults meeting DSM-IV lifetime criteria for AA but not dependence from 10 developed (n=46,071) and 11 developing (n=49,761) countries were assessed as meeting AA with the hazardous use or the social consequences criteria. RESULTS: Between 29.3% (developed) and 16.2% (developing) of respondents with AA met only the hazardous use criterion. AA cases with and without hazardous use were similar in age-of-onset, course, predictors, and psychopathological consequences in both developed and developing countries. DISCUSSION AND CONCLUSIONS: Despite some associations of the AA criteria with socioeconomic factors, the hazardous use and social consequences criteria were significantly associated with psychiatric predictors and sequelae. The findings indicate that these criteria reflect psychiatric disorder and are appropriate for inclusion as DSM-5 Alcohol Use Disorder criteria. SCIENTIFIC SIGNIFICANCE: These findings support a psychiatric rather than a sociocultural view of the hazardous use and social consequences symptoms and provide evidence that they are appropriate diagnostic criteria cross-nationally with utility in a wide range of socioeconomic environments. This suggests consideration for their adoption by ICD-11. Further research is needed on the implications of these results for prevention and treatment.

Rational design of DNA motors: fuel optimization through single-molecule fluorescence.

While numerous DNA-based molecular machines have been developed in recent years, high operational yield and speed remain a major challenge. To understand the reasons for the limited performance, and to find rational solutions, we applied single-molecule fluorescence techniques and conducted a detailed study of the reactions involved in the operation of a model system comprised of a bipedal DNA walker that strides on a DNA origami track powered by interactions with fuel and antifuel strands. Analysis of the kinetic profiles of the leg-lifting reactions indicates a pseudo-first-order antifuel binding mechanism leading to a rapid and complete leg-lifting, indicating that the fuel-removal reaction is not responsible for the 1% operational yield observed after six steps. Analysis of the leg-placing reactions showed that although increased concentrations of fuel increase the reaction rate, they decrease the yield by consecutively binding the motor and leading to an undesirable trapped state. Recognizing this, we designed asymmetrical hairpin-fuels that by regulating the reaction hierarchy avoid consecutive binding. Motors operating with the improved fuels show 74% yield after 12 consecutive reactions, a dramatic increase over the 1% observed for motors operating with nonhairpin fuels. This work demonstrates that studying the mechanisms of the reactions involved in the operation of DNA-based molecular machines using single-molecule fluorescence can facilitate rationally designed improvements that increase yield and speed and promote the applicability of DNA-based machines.

Disentangling subpopulations in single-molecule FRET and ALEX experiments with photon distribution analysis.

Among the advantages of the single-molecule approach when used to study biomolecular structural dynamics and interaction is its ability to distinguish between and independently observe minor subpopulations. In a single-molecule Förster resonance energy transfer (FRET) and alternating laser excitation diffusion experiment, the various populations are apparent in the resultant histograms. However, because histograms are calculated based on the per-burst mean FRET and stoichiometry ratio and not on the internal photon distribution, much of the acquired information is lost, thereby reducing the capabilities of the method. Here we suggest what to our knowledge is a novel statistical analysis tool that significantly enhances these capabilities, and we use it to identify and isolate static and dynamic subpopulations. Based on a kernel density estimator and a proper photon distribution analysis, for each individual burst, we calculate scores that reflect properties of interest. Specifically, we determine the FRET efficiency and brightness ratio distributions and use them to reveal 1), the underlying structure of a two-state DNA-hairpin and a DNA hairpin that is bound to DNA origami; 2), a minor doubly labeled dsDNA subpopulation concealed in a larger singly labeled dsDNA; and 3), functioning DNA origami motors concealed within a larger subpopulation of defective motors. Altogether, these findings demonstrate the usefulness of the proposed approach. The method was developed and tested using simulations, its rationality is described, and a computer algorithm is provided.

The relationships between employment, clinical status, and psychiatric hospitalisation in patients with schizophrenia receiving either IPS or a conventional vocational rehabilitation programme.

PURPOSE: Positive relationships between employment and clinical status have been found in several studies. However, an unequivocal interpretation of these relationships is difficult on the basis of common statistical methods. METHODS: In this analysis, a structural equation model approach for longitudinal data was applied to identify the direction of statistical relationships between hours worked, clinical status and days in psychiatric hospital in 312 persons with schizophrenia who participated in a multi-centre randomised controlled trial comparing the effectiveness of Individual Placement and Support (IPS) with conventional vocational services in six study settings across Europe. Data were analysed by an autoregressive cross-lagged effects model, an autoregressive cross-lagged model with random intercepts and an autoregressive latent trajectory model. RESULTS: Comparison of model fit parameters suggested the autoregressive cross-lagged effects model to be the best approach for the given data structure. All models indicated that patients who received an IPS intervention spent more hours in competitive employment and, due to indirect positive effects of employment on clinical status, spent fewer days in psychiatric hospitals than patients who received conventional vocational training. CONCLUSIONS: Results support the hypothesis that the IPS intervention has positive effects not only on vocational but also on clinical outcomes in patients with schizophrenia.

Complete, Rapid Resolution of Severe Bilateral Pneumonia and Acute Respiratory Distress Syndrome in a COVID-19 Patient: Role for a Unique Therapeutic Combination of Inhalations With Bromhexine, Higher Doses of Colchicine, and Hymecromone.

An otherwise healthy, 35-year-old man was hospitalized for the management of acute respiratory failure due to coronavirus disease 2019 (COVID-19)-related severe bilateral pneumonia and acute respiratory distress syndrome (ARDS). The patient therapeutic regimen included the widely accepted standard combination of oxygen, anticoagulation therapy; corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and antibiotics. A novel combination of colchicine, hymecromone, and bromhexine inhalations was added to the therapeutic regimen as part of our unique COVID-19 management institutional protocol. COVID-19-related severe bilateral pneumonia and acute respiratory distress syndrome (ARDS). The patient therapeutic regimen included the widely accepted standard combination of oxygen, anticoagulation therapy, corticosteroids, NSAIDs, and antibiotics. A novel combination of colchicine, hymecromone, and bromhexine inhalations was added to the therapeutic regimen as part of our unique COVID-19 management institutional protocol. Rapid clinical response on day 2, with a significant improvement of radiographic pulmonary changes on day 5, and improvement of laboratory results on days 5-7 were observed. The administration of inhalatory bromhexine in combination with high-dose colchicine and hymecromone was crucial for the positive outcome of the disease. This treatment regimen resulted in a four to five-fold decrease in the mortality of hospitalized patients.

Premarital mental disorders and physical violence in marriage: cross-national study of married couples.

BACKGROUND: Mental disorders may increase the risk of physical violence among married couples. AIMS: To estimate associations between premarital mental disorders and marital violence in a cross-national sample of married couples. METHOD: A total of 1821 married couples (3642 individuals) from 11 countries were interviewed as part of the World Health Organization's World Mental Health Survey Initiative. Sixteen mental disorders with onset prior to marriage were examined as predictors of marital violence reported by either spouse. RESULTS: Any physical violence was reported by one or both spouses in 20% of couples, and was associated with husbands' externalising disorders (OR = 1.7, 95% CI 1.2-2.3). Overall, the population attributable risk for marital violence related to premarital mental disorders was estimated to be 17.2%. CONCLUSIONS: Husbands' externalising disorders had a modest but consistent association with marital violence across diverse countries. This finding has implications for the development of targeted interventions to reduce risk of marital violence.

Treatment of suicidal people around the world.

BACKGROUND: Suicide is a leading cause of death worldwide; however, little information is available about the treatment of suicidal people, or about barriers to treatment. AIMS: To examine the receipt of mental health treatment and barriers to care among suicidal people around the world. METHOD: Twenty-one nationally representative samples worldwide (n=55 302; age 18 years and over) from the World Health Organization's World Mental Health Surveys were interviewed regarding past-year suicidal behaviour and past-year healthcare use. Suicidal respondents who had not used services in the past year were asked why they had not sought care. RESULTS: Two-fifths of the suicidal respondents had received treatment (from 17% in low-income countries to 56% in high-income countries), mostly from a general medical practitioner (22%), psychiatrist (15%) or non-psychiatrist (15%). Those who had actually attempted suicide were more likely to receive care. Low perceived need was the most important reason for not seeking help (58%), followed by attitudinal barriers such as the wish to handle the problem alone (40%) and structural barriers such as financial concerns (15%). Only 7% of respondents endorsed stigma as a reason for not seeking treatment. CONCLUSIONS: Most people with suicide ideation, plans and attempts receive no treatment. This is a consistent and pervasive finding, especially in low-income countries. Improving the receipt of treatment worldwide will have to take into account culture-specific factors that may influence the process of help-seeking.

Therapeutic relationships in vocational rehabilitation: predicting good relationships for people with psychosis.

Therapeutic relationships between clients and vocational rehabilitation workers have been shown to predict entering competitive employment. We aimed to determine predictors of good relationships, using data from an international randomized controlled trial of supported employment (n=312). Baseline predictors of early therapeutic relationships with vocational workers were assessed, along with the impact of vocational status and changing clinical and social functioning variables on relationship ratings over time. Associations between client and professional relationship ratings were also explored. Better early client-rated therapeutic relationship was predicted by better baseline relationship with the clinical keyworker, being in the Individual Placement and Support (IPS) service, the absence of work history and a greater proportion of care needs being met, whereas over time it was predicted by being in the IPS service. Professional-rated early relationship was predicted by social disability and remission, while over time it was predicted by being the same sex as the client, duration of the relationship and the client's increasing anxiety. Client and professional ratings were positively associated but clients' ratings were higher than professionals', particularly in the IPS service. Relationships were better where clients may have been more motivated to engage, including by their prior experience of a good therapeutic relationship with the clinical keyworker.

Single-molecule mechanical fingerprinting with DNA nanoswitch calipers.

Decoding the identity of biomolecules from trace samples is a longstanding goal in the field of biotechnology. Advances in DNA analysis have substantially affected clinical practice and basic research, but corresponding developments for proteins face challenges due to their relative complexity and our inability to amplify them. Despite progress in methods such as mass spectrometry and mass cytometry, single-molecule protein identification remains a highly challenging objective. Towards this end, we combine DNA nanotechnology with single-molecule force spectroscopy to create a mechanically reconfigurable DNA nanoswitch caliper capable of measuring multiple coordinates on single biomolecules with atomic resolution. Using optical tweezers, we demonstrate absolute distance measurements with ångström-level precision for both DNA and peptides, and using multiplexed magnetic tweezers, we demonstrate quantification of relative abundance in mixed samples. Measuring distances between DNA-labelled residues, we perform single-molecule fingerprinting of synthetic and natural peptides, and show discrimination, within a heterogeneous population, between different posttranslational modifications. DNA nanoswitch calipers are a powerful and accessible tool for characterizing distances within nanoscale complexes that will enable new applications in fields such as single-molecule proteomics.

Electrodelivery of drugs into cancer cells in the presence of poloxamer 188.

In the present study it is shown that poloxamer 188, added before or immediately after an electrical pulse used for electroporation, decreases the number of dead cells and at the same time does not reduce the number of reversible electropores through which small molecules (cisplatin, bleomycin, or propidium iodide) can pass/diffuse. It was suggested that hydrophobic sections of poloxamer 188 molecules are incorporated into the edges of pores and that their hydrophilic parts act as brushy pore structures. The formation of brushy pores may reduce the expansion of pores and delay the irreversible electropermeability. Tumors were implanted subcutaneously in both flanks of nude mice using HeLa cells, transfected with genes for red fluorescent protein and luciferase. The volume of tumors stopped to grow after electrochemotherapy and the use of poloxamer 188 reduced the edema near the electrode and around the subcutaneously growing tumors.

Therapeutic relationships: their specificity in predicting outcomes for people with psychosis using clinical and vocational services.

OBJECTIVE: To determine the distinctions between the client-keyworker relationship and the client-vocational worker relationship by assessing their impact on clinical outcomes and exploring the associations between the two. METHODS: As part of an international randomised controlled trial of supported employment (n = 312), client-keyworker relationship and client-vocational worker relationship were each tested against clinical and social functioning 6 months later. Associations between the two relationships over time were explored. RESULTS: Client-keyworker relationship predicted quality of life, while client-vocational worker relationship, as rated by the client, did not predict any clinical or social functioning outcomes. Vocational worker-rated relationship predicted reduced depression. The client-keyworker and client-vocational worker relationships were correlated, but this did not change over time. CONCLUSION: The impact of the client-vocational worker is likely to be on the shared task of finding employment, rather than on clinical and social functioning. Good client-vocational worker relationships do not detract from client-keyworker relationships.

Mental and neurological health research priorities setting in developing countries.

INTRODUCTION: A multi-region consultation process designed to generate locally produced regional and global research priorities on mental and neurological health in low- and middle-income countries. METHODS: Between 2003 and 2005, priority setting exercises on MNH research, using the systematic combined approach matrix (CAM) were held in the six regions of the developing world. One regional meeting per region was convened, and a global meeting was organized before and after the regional exercises. RESULTS: During regional meetings, regional agendas were created listing both research priorities and local problems in MNH. During global meetings, a global research agenda was established and four crucial areas of research priorities were identified: awareness and advocacy, enhancement of research capacity, training for service delivery, and development of evidence based policy. CONCLUSIONS: The combined matrix approach enabled the development of regional and global MNH research agendas, derived from bottom up consultations within and between low- and middle-income countries. Collaboration between regions with similar priorities was instituted. Such research agendas are designed to assist policy-makers and donors in the allocation of scarce resources, but they require regular review to reflect changing needs.

Cross-national analysis of the associations among mental disorders and suicidal behavior: findings from the WHO World Mental Health Surveys.

BACKGROUND: Suicide is a leading cause of death worldwide. Mental disorders are among the strongest predictors of suicide; however, little is known about which disorders are uniquely predictive of suicidal behavior, the extent to which disorders predict suicide attempts beyond their association with suicidal thoughts, and whether these associations are similar across developed and developing countries. This study was designed to test each of these questions with a focus on nonfatal suicide attempts. METHODS AND FINDINGS: Data on the lifetime presence and age-of-onset of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) mental disorders and nonfatal suicidal behaviors were collected via structured face-to-face interviews with 108,664 respondents from 21 countries participating in the WHO World Mental Health Surveys. The results show that each lifetime disorder examined significantly predicts the subsequent first onset of suicide attempt (odds ratios [ORs] = 2.9-8.9). After controlling for comorbidity, these associations decreased substantially (ORs = 1.5-5.6) but remained significant in most cases. Overall, mental disorders were equally predictive in developed and developing countries, with a key difference being that the strongest predictors of suicide attempts in developed countries were mood disorders, whereas in developing countries impulse-control, substance use, and post-traumatic stress disorders were most predictive. Disaggregation of the associations between mental disorders and nonfatal suicide attempts showed that these associations are largely due to disorders predicting the onset of suicidal thoughts rather than predicting progression from thoughts to attempts. In the few instances where mental disorders predicted the transition from suicidal thoughts to attempts, the significant disorders are characterized by anxiety and poor impulse-control. The limitations of this study include the use of retrospective self-reports of lifetime occurrence and age-of-onset of mental disorders and suicidal behaviors, as well as the narrow focus on mental disorders as predictors of nonfatal suicidal behaviors, each of which must be addressed in future studies. CONCLUSIONS: This study found that a wide range of mental disorders increased the odds of experiencing suicide ideation. However, after controlling for psychiatric comorbidity, only disorders characterized by anxiety and poor impulse-control predict which people with suicide ideation act on such thoughts. These findings provide a more fine-grained understanding of the associations between mental disorders and subsequent suicidal behavior than previously available and indicate that mental disorders predict suicidal behaviors similarly in both developed and developing countries. Future research is needed to delineate the mechanisms through which people come to think about suicide and subsequently progress from ideation to attempts.

Working with mental health problems: clients' experiences of IPS, vocational rehabilitation and employment.

BACKGROUND: Although the effectiveness of individual placement and support (IPS) has been well established, little is known about clients' perceptions of the model compared to usual vocational rehabilitation, nor about their experiences of searching for and returning to work with this kind of support. This qualitative study aimed to explore clients' views of the difficulties of obtaining and maintaining employment, their experiences of the support received from their IPS or Vocational Service workers and the perceived impact of work on clients' lives. METHOD: Semi-structured interviews were conducted with 48 people with psychotic disorders participating in a six-centre international randomised controlled trial of IPS compared to usual vocational rehabilitation. To assess their experiences of the services and the perceived effects of working, two IPS and two Vocational Service clients at each centre who had found work during the study period were interviewed, along with two IPS and two Vocational Service clients at each centre who had not. RESULTS: IPS clients reported having received more help seeking and maintaining employment, whereas Vocational Service clients reported having received more help in finding sheltered employment or placements. Clients who had worked associated this with financial stability, improved social lives, increased self-esteem, integration into society and amelioration of their symptoms, as well as reduced feelings of boredom and isolation, but also reported increased levels of stress. IPS clients as well as Vocational Service ones reported not receiving enough follow-up support, despite this being proposed as a key feature of the model. CONCLUSION: Findings from the in-depth interviews reflect differences in service models that have also been tested quantitatively but further work in disaggregating the IPS model and assessing the impact of each component would be valuable.