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Background: People with severe mental illnesses are often excluded from working life and would like support to (re)enter the general labor market as part of the psychiatric treatment. Individual placement and support (IPS) is an effective method of finding and retaining work in the general labor market. The aim of the study was to determine the integration rates of IPS into the general labor market in acute and postacute psychiatric settings, identifying patient, setting and program characteristics associated with (re)entering work., Method: A retrospective chart review (RCR) of routine clinical data between 2016 and 2021 was carried out. The IPS program adherence was rated using the IPS fidelity scale., Results: A total of 375 patients participated in the IPS with at least 4 appointments. The (re)integration rate into the general labor market was 51.7%. A shorter time period to the last working day, diagnosis of F1, F2, F3 (vs. F4), change of treatment setting and IPS in the psychiatric institute outpatient department (PIA), IPS fidelity and the number of IPS coaching sessions were positively correlated with (re)integration into work., Conclusion: The implementation of IPS in clinical mental healthcare is possible and leads to high integration rates in the open labor market. An early start of IPS during the clinical treatment can promote social inclusion., (© 2024. The Author(s).)

Aim: A substantial gap between young people's need for mental health care services and their actual access to such services led worldwide organizations (e.g., the WHO) to recommend the implementation of early intervention programs and youth mental health services. Some countries around the world have established structures to meet this recommendation. In this paper, we describe soulspace as the first integrated youth mental health service for young people aged between 15 and 35 years in Berlin, Germany., Methods: We introduce soulspace as easily accessible mental health care for young people, and we characterize soulspace along the lines of the internationally established eight key principles of integrated youth mental health services (Killackey, et al., 2020, World Economic Forum). Soulspace is a cooperation between clinical outpatient units of psychiatric clinics for adolescents and young adults as well as a community-based counselling service. It provides initial contact, counselling, diagnostics, and treatment., Results: Our analyses of the pathways to soulspace and the characteristics of the soulspace users suggest that the low threshold is a facilitator to help finding for young people in comparison to more conventional early intervention models. That is, having transferred the early intervention center in a youth-facing counselling service as was done in soulspace seems to have reduced the threshold to seek help for families and for young people in need for support., Conclusions: In summary, with soulspace, an easily accessible mental health care service was established that integrates counselling and specialized psychiatric treatment if needed., (© 2024 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Objective: To assess work-related participation impairments and support needs of adult patients in inpatient and day-care treatment at a Swiss psychiatric university hospital., Methodology: Cross-sectional survey on a department-dependent cut-off date in May and June 2022 using a standardized structured interview., Results: Data were available for 93 patients (response rate 59%), of which 51% ( n = 47) stated that they had a job or training place. Patients in first hospitalization and with a job or training place were approached significantly more often. Regardless of age and first hospitalization, 76% of the patients expressed a need for support, of which 92% expressed interest in job coaching. A total of 54% of the patients stated that they had received support from the treatment team., Conclusion: From the patients' point of view, work and education were not addressed by the treatment team across the board and independently of patient characteristics. The need for support was insufficiently met. There is a considerable interest for support programs through job coaching, and this offers opportunities to promote the inclusion of patients in the regular labor market., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hug, Imfeld, Holinger, Jäckel, Huber and Nienaber.)

Objective: Evaluation of long-term effects of the implementation of the Safewards Model (SM) among staff and patients in acute psychiatry in Germany., Method: Assessment of ward atmosphere, job satisfaction, fidelity, and coercive interventions in 2 locked wards directly before and 15 months after implementation of the SM., Results: Ward atmosphere was assessed significantly better after implementation, job satisfaction was still above-average at both times, coercive interventions declined significantly in one ward, fidelity and degree of implementation were still high., Conclusions: The implementing of the SM in locked wards in acute psychiatry can also have positive effects in long run., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Citizen Science (CS) is a research approach that has become popular in recent years and offers innovative potential for dialect research in ornithology. As the scepticism about CS data is still widespread, we analysed the development of a 3-year CS project based on the song of the Common Nightingale ( Luscinia megarhynchos ) to share best practices and lessons learned. We focused on the data scope, individual engagement, spatial distribution and species misidentifications from recordings generated before (2018, 2019) and during the COVID-19 outbreak (2020) with a smartphone using the 'Naturblick' app. The number of nightingale song recordings and individual engagement increased steadily and peaked in the season during the pandemic. 13,991 nightingale song recordings were generated by anonymous (64%) and non-anonymous participants (36%). As the project developed, the spatial distribution of recordings expanded (from Berlin based to nationwide). The rates of species misidentifications were low, decreased in the course of the project (10-1%) and were mainly affected by vocal similarities with other bird species. This study further showed that community engagement and data quality were not directly affected by dissemination activities, but that the former was influenced by external factors and the latter benefited from the app. We conclude that CS projects using smartphone apps with an integrated pattern recognition algorithm are well suited to support bioacoustic research in ornithology. Based on our findings, we recommend setting up CS projects over the long term to build an engaged community which generates high data quality for robust scientific conclusions., Supplementary Information: The online version contains supplementary material available at 10.1007/s10336-022-02018-8., Competing Interests: Conflict of interestThis work was supported by BMBF (Förderkennzeichen: 01BF1709). The authors have no relevant financial or non-financial interests to disclose. The authors have no competing interests to declare that are relevant to the content of this article. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript. The authors have no financial or proprietary interests in any material discussed in this article., (© The Author(s) 2022.)

Knowledge of hearing ability, as represented in audiograms, is essential for understanding how animals acoustically perceive their environment, predicting and counteracting the effects of anthropogenic noise, and managing wildlife. Audiogram data and relevant background information are currently only available embedded in the text of individual scientific publications in various unstandardized formats. This heterogeneity makes it hard to access, compare, and integrate audiograms. The Animal Audiogram Database (https://animalaudiograms.org) assembles published audiogram data, metadata about the corresponding experiments, and links to the original publications in a consistent format. The database content is the result of an extensive survey of the scientific literature and manual curation of the audiometric data found therein. As of November 1, 2021, the database contains 306 audiogram datasets from 34 animal species. The scope and format of the provided metadata and design of the database interface were established by active research community involvement. Options to compare audiograms and download datasets in structured formats are provided. With the focus currently on vertebrates and hearing in underwater environments, the database is drafted as a free and open resource for facilitating the review and correction of the contained data and collaborative extension with audiogram data from any taxonomic group and habitat.

The effects of mental diseases on the employment and working situation can be substantial. They are one of the main reasons for inability to work and reduced earning capacity. Against this background the question arises about suitable occupational reintegration measures for people with severe mental illnesses. In recent years, the principle of supported employment has been internationally shown to be increasingly more successful. In this context mentally ill people are primarily placed at a position of the first employment market and supported on-site by a job coach. This concept is inclusive, individual and evidence based. Despite proven effectiveness, it has so far been insufficiently implemented in German-speaking regions. In the future it will be a matter of considering the individual needs for assistance of mentally ill people more intensively than previously and to respond with functional and in a best-case scenario, multiprofessional and flexible offers., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Citizen science is an approach that has become increasingly popular in recent years. Despite this growing popularity, there still is widespread scepticism in the academic world about the validity and quality of data from citizen science projects. And although there might be great potential, citizen science is a rarely used approach in the field of bioacoustics. To better understand the possibilities, but also the limitations, we here evaluated data generated in a citizen science project on nightingale song as a case study. We analysed the quantity and quality of song recordings made in a non-standardized way with a smartphone app by citizen scientists and the standardized recordings made with professional equipment by academic researchers. We made comparisons between the recordings of the two approaches and among the user types of the app to gain insights into the temporal recording patterns, the quantity and quality of the data. To compare the deviation of the acoustic parameters in the recordings with smartphones and professional devices from the original song recordings, we conducted a playback test. Our results showed that depending on the user group, citizen scientists produced many to a lot of recordings of valid quality for further bioacoustic research. Differences between the recordings provided by the citizen and the expert group were mainly caused by the technical quality of the devices used-and to a lesser extent by the citizen scientists themselves. Especially when differences in spectral parameters are to be investigated, our results demonstrate that the use of the same high-quality recording devices and calibrated external microphones would most likely improve data quality. We conclude that many bioacoustic research questions may be carried out with the recordings of citizen scientists. We want to encourage academic researchers to get more involved in participatory projects to harness the potential of citizen science-and to share scientific curiosity and discoveries more directly with society., Competing Interests: The authors have declared that no competing interests exist.

Objective: Approximately 80 % of patients in psychiatric treatment are significant impaired in participation work and are excluded from the labor market., Method: Survey of 176 patients in day hospital and inpatient psychiatric treatment regarding work-related participation impairments, need for support in competitive employment, education or study and actually received support., Results: Data of 90 patients were available. 63 % of patients indicated a need for support in work-related participation, 53 % of them would participate in a job coaching. 49 % of the patients were addressed on the topic of work. Regardless of the need for support, only 1/5 of patients received concrete help. There is a strong need for support for young adults (77 %) and first-admission patients (73 %)., Conclusion: There is a high but unmet need for support in managing work-related participation impairment. Routine needs assessment and the implementation of evidence-based methods could improve work-related inclusion., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Evaluation of the changes of ward atmosphere and job satisfaction after the implementation of the Safewards model in acute psychiatry in Germany., Method: A multi-perspective pre-post study design was conducted in two locked wards among patients (n = 80) and staff (n = 88) before and after the implementation of the Safewards model over a period of 12 months., Results: After the implementation of the Safewards model, ward atmosphere and job satisfaction improved. Both correlated positively amongst staff. Furthermore, job satisfaction correlated positively with a high degree of implementation of two interventions. Fidelity to the Safewards model was high., Conclusions: Implementing the Safewards model in acute psychiatry with high fidelity can have positive effects on positive ward atmosphere and job satisfaction. Thus, patients as well as staff benefit from this model. With regards to high fluctuation in acute psychiatry, the implementation of the Safewards model can additionally facilitate retention management., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Aggression and violence are highly complex problems in acute psychiatry that often lead to the coercive interventions. The Safewards Model is an evidence-informed conflict-reduction strategy to prevent and reduce such incidents. The aim of this study was to evaluate the implementation of this model with regard to coercive interventions in inpatient care. Materials and Methods: We evaluated outcomes of the implementation of the Safewards Model in two locked psychiatric wards in Germany. Frequency and duration of coercive interventions applied during a period of 10 weeks before and 10 weeks after the implementation period were assessed through routine data. Fidelity to the Safewards Model was assessed by the Organization Fidelity Checklist. Results: Fidelity to the Safewards Model was high in both wards. The overall use of coercive measures differed significantly between wards [case-wise: χ 2 (1, n = 250) = 35.34, p ≤ 0.001; patient-wise: χ 2 (1, n = 103) = 21.45, p ≤ 0.001] and decreased post-implementation. In one ward, the number of patients exposed to coercive interventions in relation to the overall number of admissions decreased significantly [χ 2 (1, 182) = 9.30, p = 0.003]. Furthermore, the mean duration of coercive interventions overall declined significantly [ U (55,21) = -2.142, p = 0.032] with an effect size of Cohen's d = -0.282 (95% CI: -0.787, 0.222) in that ward. Both aspects declined as well in the other ward, but not significantly. Discussion: Results indicate that the implementation of the Safewards interventions according to the model in acute psychiatric care can reduce coercive measures. They also show the role of enabling factors as well as of obstacles for the implementation process.

Extracellular voltage fields, produced by a neuron's action potentials, provide a widely used means for studying neuronal and neuronal-network function. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP) landscape, while the axon's contribution is usually considered less important. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices through hundreds of densely packed electrodes, it is found, instead, that the axon initial segment dominates the measured EAP landscape, and, surprisingly, the soma only contributes to a minor extent. As expected, the recorded dominant signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage landscape is important for interpreting results from all electrical readout schemes. Finally, initiation of the electrical activity at the distal end of the axon initial segment (AIS) and subsequent spreading into the axon proper and backward through the proximal AIS toward the soma are confirmed. The corresponding extracellular waveforms across different neuronal compartments could be tracked., Competing Interests: Conflict of Interest M.E.J.O. and U.F. are cofounders of MaxWell Biosystems AG, Mattenstrasse 26, c/o ETH Zurich, Basel 4058, Switzerland. D.J. is now employed at MaxWell Biosystems AG.

Background: The present study evaluated service use of our newly established Early Intervention and Treatment Centre (FRITZ) in Berlin for young adults with first or early psychosis with and without migration background., Methods: We conducted a retrospective chart review of in-patients with early psychosis who were admitted to FRITZ between May 2014 and May 2015. We investigated the proportion of patients with migration background, sociodemographic and clinical characteristics of patients., Results: Corresponding to the proportion of migrants in the catchment area, 35 % of our service users from the catchment area (n = 60) had a migration background. Migrants had a better social adaption, but showed lower insight into illness, less substance induced psychoses and less inpatient admissions. The majority of all patients were admitted to FRITZ via the emergency department., Conclusions: The findings indicate that FRITZ was almost equally well received by patients with and without migration background. Patients with migration background showed distinct sociodemographic and clinical characteristics that could be relevant for treatment. Implications for future clinical practice are discussed., Competing Interests: Andreas Bechdolf: Vortragshonorare, Reisestipendien von Janssen Cillag, Lilly, Lundbeck, Otsuka. Forschungsförderung von Otsuka, DFG , BMBF, NARSAD und Janssen Cillag.Karolina Leopold: Vortragshonorare, Reisestipendien von AstraZeneca, Janssen Cillag, Lilly, Lundbeck, Otsuka, Pfizer. Forschungsförderung von Otsuka, AstraZeneca und Janssen Cillag., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Organ transplant recipients have an up to 250-times higher risk to develop skin cancer. This article evaluated the utilisation of skin cancer screening and the treatment costs for skin cancer in organ transplant recipients. Patients of the health insurance AOK Bremen/Bremerhaven had been identified and the need for skin cancer prevention trainings was derived., Methods: The number of organ transplant recipients (ICD code Z94.0-4) with and without any history of skin cancer (ICD code C43/C44), the utilisation of dermatologic health care services, and the costs for treatments with the diagnosis Z94.0-4 with and without C43/C44 were evaluated. The analyses were carried out for the period from 2009-2014 by using the accounting systems of the AOK., Results: Between 2009 and 2014, 231 organ transplant recipients had been recorded. By mid-2014, 20% of these insured persons developed skin cancer and the mean incidence was 2.76% per year. On average, 43% of these patients were seen by a dermatologist at least once a year, whereby only 15% of the organ transplant recipients participated in the annual skin cancer screening. In 29% of the patients without any history of skin cancer, a skin examination was never performed by a dermatologist or a general practitioner. In all, 17 inpatient cases of organ transplant recipients with the primary diagnosis C43/C44 were analyzed. This resulted in total costs of 54,707 € (on average about 3200 € per case)., Conclusions: The increased incidence of skin cancer and the associated treatment costs indicate the need for skin cancer prevention training.

Objective: There is extensive evidence for the effectiveness of supported employment among people with severe mental illness. However, less research has been conducted to evaluate the effects of sustained competitive employment on nonvocational outcomes. The aim of this study was to evaluate the effects of sustained competitive work on quality of life and psychiatric hospitalizations., Methods: As part of a randomized controlled trial, a mediation analysis was used to compare the direct and indirect effects of supported employment versus a traditional vocational program on sustained competitive employment, days of psychiatric hospitalization, and quality of life among 85 participants over five years., Results: The five-year follow-up indicated that the effects of supported employment on reduced days of hospitalization and increased quality of life were fully mediated by the program's effects on increasing sustained competitive employment., Conclusions: The rehabilitative and therapeutic dimensions of functional health conditions are interrelated in the long term. The achievement of sustained competitive employment may be a key factor in improving social and psychiatric outcomes for people with severe and persistent mental disorders.

We present a novel, all-electric approach to record and to precisely control the activity of tens of individual presynaptic neurons. The method allows for parallel mapping of the efficacy of multiple synapses and of the resulting dynamics of postsynaptic neurons in a cortical culture. For the measurements, we combine an extracellular high-density microelectrode array, featuring 11'000 electrodes for extracellular recording and stimulation, with intracellular patch-clamp recording. We are able to identify the contributions of individual presynaptic neurons - including inhibitory and excitatory synaptic inputs - to postsynaptic potentials, which enables us to study dendritic integration. Since the electrical stimuli can be controlled at microsecond resolution, our method enables to evoke action potentials at tens of presynaptic cells in precisely orchestrated sequences of high reliability and minimum jitter. We demonstrate the potential of this method by evoking short- and long-term synaptic plasticity through manipulation of multiple synaptic inputs to a specific neuron.

A novel system to cultivate and record from organotypic brain slices directly on high-density microelectrode arrays (HD-MEA) was developed. This system allows for continuous recording of electrical activity of specific individual neurons at high spatial resolution while monitoring at the same time, neuronal network activity. For the first time, the electrical activity patterns of single neurons and the corresponding neuronal network in an organotypic hippocampal slice culture were studied during several consecutive weeks at daily intervals. An unsupervised iterative spike-sorting algorithm, based on PCA and k-means clustering, was developed to assign the activities to the single units. Spike-triggered average extracellular waveforms of an action potential recorded across neighboring electrodes, termed "footprints" of single-units were generated and tracked over weeks. The developed system offers the potential to study chronic impacts of drugs or genetic modifications on individual neurons in slice preparations over extended times.

A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs.

Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells' signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations.

Knowledge of neuronal cell types in the mammalian retina is important for the understanding of human retinal disease and the advancement of sight-restoring technology, such as retinal prosthetic devices. A somewhat less utilized animal model for retinal research is the hamster, which has a visual system that is characterized by an area centralis and a wide visual field with a broad binocular component. The hamster retina is optimally suited for recording on the microelectrode array (MEA), because it intrinsically lies flat on the MEA surface and yields robust, large-amplitude signals. However, information in the literature about hamster retinal ganglion cell functional types is scarce. The goal of our work is to develop a method featuring a high-density (HD) complementary metal-oxide-semiconductor (CMOS) MEA technology along with a sequence of standardized visual stimuli in order to categorize ganglion cells in isolated Syrian Hamster (Mesocricetus auratus) retina. Since the HD-MEA is capable of recording at a higher spatial resolution than most MEA systems (17.5 μm electrode pitch), we were able to record from a large proportion of RGCs within a selected region. Secondly, we chose our stimuli so that they could be run during the experiment without intervention or computation steps. The visual stimulus set was designed to activate the receptive fields of most ganglion cells in parallel and to incorporate various visual features to which different cell types respond uniquely. Based on the ganglion cell responses, basic cell properties were determined: direction selectivity, speed tuning, width tuning, transience, and latency. These properties were clustered to identify ganglion cell types in the hamster retina. Ultimately, we recorded up to a cell density of 2780 cells/mm(2) at 2 mm (42°) from the optic nerve head. Using five parameters extracted from the responses to visual stimuli, we obtained seven ganglion cell types.

A novel system to cultivate and record brain slices directly on high-density microelectrode arrays (HD-MEA) was developed. This system allows to continuously record electrical activity of selected individual neurons at high spatial resolution, while monitoring neuronal network activity at the same time. For the first time, properties of single neurons and the corresponding neuronal network in an organotypic hippocampal slice culture were studied over four consecutive weeks at daily intervals.

To advance our understanding of the functioning of neuronal ensembles, systems are needed to enable simultaneous recording from a large number of individual neurons at high spatiotemporal resolution and good signal-to-noise ratio. Moreover, stimulation capability is highly desirable for investigating, for example, plasticity and learning processes. Here, we present a microelectrode array (MEA) system on a single CMOS die for in vitro recording and stimulation. The system incorporates 26,400 platinum electrodes, fabricated by in-house post-processing, over a large sensing area (3.85 × 2.10 mm 2 ) with sub-cellular spatial resolution (pitch of 17.5 μm). Owing to an area and power efficient implementation, we were able to integrate 1024 readout channels on chip to record extracellular signals from a user-specified selection of electrodes. These channels feature noise values of 2.4 μV rms in the action-potential band (300 Hz-10 kHz) and 5.4 μV rms in the local-field-potential band (1 Hz-300 Hz), and provide programmable gain (up to 78 dB) to accommodate various biological preparations. Amplified and filtered signals are digitized by 10 bit parallel single-slope ADCs at 20 kSamples/s. The system also includes 32 stimulation units, which can elicit neural spikes through either current or voltage pulses. The chip consumes only 75 mW in total, which obviates the need of active cooling even for sensitive cell cultures.

Objective: The individual placement and support model of supported employment has been shown to be more effective than other vocational approaches in improving competitive work over 1-2 years in persons with severe mental illness. The authors evaluated the longer-term effects of the model compared with traditional vocational rehabilitation over 5 years., Method: A randomized controlled trial compared supported employment to traditional vocational rehabilitation in 100 unemployed persons with severe mental illness. Competitive work and hospital admissions were tracked for 5 years, and interviews were conducted at 2 and 5 years to assess recovery attitudes and quality of life. A cost-benefit analysis compared program and total treatment costs to earnings from competitive employment., Results: The beneficial effects of supported employment on work at 2 years were sustained over the 5-year follow-up period. Participants in supported employment were more likely to obtain competitive work than those in traditional vocational rehabilitation (65% compared with 33%), worked more hours and weeks, earned more wages, and had longer job tenures. Reliance on supported employment services for retaining competitive work decreased from 2 years to 5 years for participants in supported employment. Participants were also significantly less likely to be hospitalized, had fewer psychiatric hospital admissions, and spent fewer days in the hospital. The social return on investment was higher for supported employment participants, whether calculated as the ratio of work earnings to vocational program costs or of work earnings to total vocational program and mental health treatment costs., Conclusions: The results demonstrate that the greater effectiveness of supported employment in improving competitive work outcomes is sustained beyond 2 years and suggest that supported employment programs contribute to reduced hospitalizations and produce a higher social return on investment.

Spike overlaps occur frequently in dense neuronal network recordings, creating difficulties for spike sorting. Brainmachine interfaces and in vivo studies of neuronal network dynamics often require that an accurate spike sorting be done in real time, with low execution latency (on the order of milliseconds). Moreover, modern neuronal recording systems that feature thousands of electrodes require processing of several tens or hundreds of neurons in parallel. The existing algorithms capable of performing spike overlap decomposition are generally very complex and unsuitable for real-time implementation, especially for an on-chip implementation. Here we present a hardware device capable of processing pair-wise spike overlaps in real time. A previously-published spike sorting algorithm, which is not suitable for processing data of large neuronal networks with low latency, has been optimized for high-throughput, low-latency hardware implementation. The designed hardware architecture has been verified on an FPGA platform. Low spike sorting error rates (0.05) for overlapping spikes have been achieved with a latency of 2.75 ms, rendering the system particularly suitable for use in closed-loop experiments.

Emerging multi-electrode-based brain-machine interfaces (BMIs) and large multi-electrode arrays used in in vitro experiments, enable recording of single neuron's activity on multiple electrodes and allow for an in-depth investigation of neural preparations, even at a sub-cellular level. However, the use of these devices entails stringent area and power consumption constraints for the signal-processing hardware units. In addition, the high autonomy of these units and an ability to automatically adapt to changes in the recorded neural preparations is required. Implementing spike detection in close proximity to recording electrodes offers the advantage of reducing the transmission data bandwidth. By eliminating the need of transmitting the full, redundant recordings of neural activity and by transmitting only the spike waveforms or spike times, significant power savings can be achieved in the majority of cases. Here, we present a low-complexity, unsupervised, adaptable, real-time spike-detection method targeting multi-electrode recording devices and compare this method to other spike-detection methods with regard to complexity and performance.

Understanding plasticity of neural networks is a key to comprehending their development and function. A powerful technique to study neural plasticity includes recording and control of pre- and post-synaptic neural activity, e.g., by using simultaneous intracellular recording and stimulation of several neurons. Intracellular recording is, however, a demanding technique and has its limitations in that only a small number of neurons can be stimulated and recorded from at the same time. Extracellular techniques offer the possibility to simultaneously record from larger numbers of neurons with relative ease, at the expenses of increased efforts to sort out single neuronal activities from the recorded mixture, which is a time consuming and error prone step, referred to as spike sorting. In this mini-review, we describe recent technological developments in two separate fields, namely CMOS-based high-density microelectrode arrays, which also allow for extracellular stimulation of neurons, and real-time spike sorting. We argue that these techniques, when combined, will provide a powerful tool to study plasticity in neural networks consisting of several thousand neurons in vitro.

In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic-configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14±7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings.

Although tumors express potentially immunogenic tumor-associated antigens (TAAs), cancer vaccines often fail because of inadequate antigen delivery and/or insufficient activation of innate immunity. Engineering nonpathogenic bacterial vectors to deliver TAAs of choice may provide an efficient way of presenting TAAs in an immunogenic form. In this study, we used genes of Salmonella pathogenicity island 2 (SPI2) to construct a novel cancer vaccine in which a TAA, survivin, was fused to SseF effector protein and placed under control of SsrB, the central regulator of SPI2 gene expression. This construct uses the type III secretion system (T3SS) of Salmonella and allows preferential delivery of tumor antigen into the cytosol of antigen-presenting cells for optimal immunogenicity. In a screen of a panel of attenuated strains of Salmonella, we found that a double attenuated strain of Salmonella typhimurium, MvP728 (purD/htrA), was not toxic to mice and effectively expressed and translocated survivin protein inside the cytosol of murine macrophages. We also found that a ligand for CD1d-reactive natural killer T (NKT) cells, alpha-glucuronosylceramide (GSL1), enhanced MvP728-induced interleukin-12 production in human dendritic cells and that in vivo coadministration of a NKT ligand with MvP728-Llo or MvP728-survivin enhanced effector-memory cytotoxic T lymphocyte (CTL) responses. Furthermore, combined use of MvP728-survivin with GSL1 produced antitumor activity in mouse models of CT26 colon carcinoma and orthotopic DBT glioblastoma. Therefore, the use of TAA delivery via SPI-2-regulated T3SS of Salmonella and NKT ligands as adjuvants may provide a foundation for new cancer vaccines.

The virulence of Salmonella enterica critically depends on the functions of two type III secretion systems (T3SS), with the Salmonella pathogenicity island 1 (SPI1)-encoded T3SS required for host cell invasion and the SPI2-T3SS enabling Salmonella to proliferate within host cells. A further T3SS is required for the assembly of the flagella. Most serovars of Salmonella also possess a lipopolysaccharide with a complex O-antigen (OAg) structure. The number of OAg units attached to the core polysaccharide varies between 16 and more than 100 repeats, with a trimodal distribution. This work investigated the correlation of the OAg length with the functions of the SPI1-T3SS and the SPI2-T3SS. We observed that the number of repeats of OAg units had no effect on bacterial motility. The interaction of Salmonella with epithelial cells was altered if the OAg structure was changed by mutations in regulators of OAg. Strains defective in synthesis of very long or long and very long OAg species showed increased translocation of a SPI1-T3SS effector protein and increased invasion. Invasion of a strain entirely lacking OAg was increased, but this mutant strain also showed increased adhesion. In contrast, translocation of a SPI2-T3SS effector protein and intracellular replication were not affected by modification of the OAg length. Mutant strains lacking the entire OAg or long and very long OAg were highly susceptible to complement killing. These observations indicate that the architecture of the outer membrane of Salmonella is balanced to permit sufficient T3SS function but also to confer optimal protection against antimicrobial defense mechanisms.

Recombinant engineering using Red recombinase-based approaches offers efficient and rapid approaches to deletion and modification of genes. Here we describe a novel application of Red recombinant engineering that enables direct manipulation of chromosomal loci by electroporation with short synthetic DNA molecules. We demonstrate the use of this approach for the generation of scarless in-frame deletions in chromosomal genes of Salmonella enterica. Furthermore, we describe rapid site-directed mutagenesis within bacterial chromosomes without any requirement for cloning and mutating genes in vitro or for reintroducing mutant alleles into the chromosome. This approach can be expected to facilitate mutational analysis in S. enterica and in other bacterial species able to support Red-mediated recombination.

Invasion is an important microbial virulence strategy to overcome the barrier formed by polarized epithelial cells. Salmonella enterica is a food-borne pathogen that deploys a type III secretion system for the manipulation of the actin cytoskeleton and to trigger internalization into epithelial cells. Here we show that this function is not sufficient to enter polarized cells and report that penetration of epithelia from the luminal side requires both the type III secretion system and novel virulence functions conferred by Salmonella pathogenicity island 4. Salmonella pathogenicity island 4 encodes a type I secretion system for the giant non-fimbrial adhesin SiiE that mediates intimate contact of Salmonella to microvilli on the apical membrane. Mutant strains lacking SiiE fail to invade polarized cells, to destroy epithelial barrier functions and to efface the apical brush border. Deletion analyses of repetitive domains in SiiE indicate that the large size of the adhesin is of functional importance. Our observations demonstrate that efficient penetration of epithelial barriers requires the cooperative activity of two Salmonella pathogenicity islands encoding different secretion systems. These findings underline the role of the epithelial brush border and reveal a new mechanism used by bacterial pathogens to overcome this barrier.

Salmonella pathogenicity island 4 (SPI4) encodes a type I secretion system and the cognate substrate protein, SiiE. We have recently demonstrated that SiiE is a giant nonfimbrial adhesin involved in the adhesion of Salmonella enterica serovar Typhimurium to polarized epithelial cells. We also observed that under in vitro culture conditions, the synthesis and secretion of SiiE coincided with the activation of Salmonella invasion genes. These observations prompted us to investigate the regulation of SPI4 genes in detail. A novel approach for the generation of reporter gene fusions was employed to generate single-copy chromosomal fusions to various genes within SPI4, and the expression of these fusions was investigated. We analyzed the regulation of SPI4 genes and the roles of various regulatory systems for SPI4 expression. Our data show that the expression of SPI4 genes is coregulated with SPI1 invasion genes by the global regulator SirA. Expression of a SPI4 gene was also reduced in the absence of HilA, the central local regulator of SPI1 gene expression. Both SirA and HilA functions were required for the secretion of SiiE and the SPI4-mediated adhesion. Our data demonstrate that SPI4-mediated adhesion, as well as SPI1-mediated invasion, are tightly coregulated by the same regulatory circuits and induced under similar environmental conditions.

Reporter gene fusions are essential tools for the investigation of gene regulation. Such fusions are traditionally generated by transposon mutagenesis and identified by a suitable selection procedure. Alternatively, specific reporter fusions can be generated by cloning of DNA fragments containing promoters or other regulatory elements in reporter plasmids. Here, we describe a novel approach for the rapid generation of reporter gene fusions in single copies at defined positions in bacterial genomes. This technique utilizes the Red recombinase for the homologous recombination of PCR-generated cassettes containing various currently used reporter genes, such as those for beta-galactosidase, luciferase, and green fluorescent protein. The approach allows the generation of transcriptional or translational reporter fusions in a single step without the requirement for recombinant DNA constructs and is applicable to various enterobacterial species. Generation of reporter fusions by Red recombination is rapid, overcomes the current limitations of transposon mutagenesis or reporter plasmids, and offers new options for the study of bacterial gene regulation.