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Although automated spoken language assessment is rapidly growing, such systems have not been widely developed for signed languages. This study provides validity evidence for an automated web application that was developed to assess and give feedback on handshape and hand movement of L2 learners' Swiss German Sign Language signs. The study shows good machine-internal and human-machine agreement through many-facet Rasch analysis. Learner perceptions examined through questionnaire responses indicate that the automated system occasionally generated ratings which impacted the quality of feedback at the level of individual signs for individual learners. Implications are discussed from a learning-oriented assessment perspective.

Sign languages present particular challenges to language assessors in relation to variation in signs, weakly defined citation forms, and a general lack of standard-setting work even in long-established measures of productive sign proficiency. The present article addresses and explores these issues via a mixed-methods study of a human-rated form-recall sign vocabulary test of 98 signs for beginning adult learners of Swiss German Sign Language (DSGS), using post-test qualitative rater interviews to inform interpretation of the results of quantitative analysis of the test ratings using many-facets Rasch measurement. Significant differences between two expert raters were observed on three signs. The follow-up interview revealed disagreement on the criterion of correctness, despite the raters' involvement in the development of the base lexicon of signs. The findings highlight the challenges of using human ratings to assess the production not only of sign language vocabulary, but of minority languages generally, and underscore the need for greater effort expended on the standardization of sign language assessment.

In German Switzerland the learning and assessment of Swiss German Sign Language ("Deutschschweizerische Gebärdensprache," DSGS) takes place in different contexts, for example, in tertiary education or in continuous education courses. By way of the still ongoing implementation of the Common European Framework of Reference for DSGS, different tests and assessment procedures are currently been developed and their potential is explored to support the learning and assessment of DSGS. Examples of this are two vocabulary size tests. The first is a web-delivered Yes/No Test, the second a Translation Test from written German to DSGS. For both tests, the same set of items was used. The items were sampled from DSGS teaching materials. For the development of the two vocabulary size tests, 20 DSGS adult learners of ages 24 to 55 (M = 39.3) were recruited as test takers. An item analysis of the test results yielded candidates for removal from the item set. Cronbach's Alpha showed good results for both tests (>0.90), and inter-rater reliability of the Translation Test also indicated promising results (Cohen's Kappa = 0.613, p <0.001). Evidence contributing to content validity was collected based on the sampling method of the test items. Due to the lack of a second DSGS vocabulary test that could be used to establish concurrent validity, external variables were identified and investigated as possible external criteria contributing to the performance of the test takers. One variable, number of courses attended, showed a significant correlation with the test results.

In this study we seek evidence of validity according to the socio-cognitive framework (Weir, 2005) for a new sentence repetition test (SRT) for young Deaf L1 Swiss German Sign Language (DSGS) users. SRTs have been developed for various purposes for both spoken and sign languages to assess language development in children. In order to address the need for tests to assess the grammatical development of Deaf L1 DSGS users in a school context, we developed an SRT. The test targets young learners aged 6-17 years, and we administered it to 46 Deaf students aged 6.92-17.33 (M = 11.17) years. In addition to the young learner data, we collected data from Deaf adults (N = 14) and from a sub-sample of the children (n = 19) who also took a test of DSGS narrative comprehension, serving as a criterion measure. We analyzed the data with many-facet Rasch modeling, regression analysis, and analysis of covariance. The results show evidence of scoring, criterion, and context validity, suggesting the suitability of the SRT for the intended purpose, and will inform the revision of the test for future use as an instrument to assess the sign language development of Deaf children.

Background: Occupational stress is one of the main sources of stress in apprentices with physical and psychological health consequences. Just‐in‐time planning interventions (JITPIs) are one opportunity to deliver intervention components at the right times and locations to optimally support apprentices in stressful situations. The aim of this study was to test the proximal effect of a mobile phone‐delivered JITPI to reduce occupational stress in 386 apprentices within a planning intervention. Methods: An AB/BA crossover design in which participants were randomly allocated to (A) the planning intervention or (B) the assessment only condition was implemented. Results: The analyses of the study "ready4life", multilevel modeling, revealed no significant effect of the planning intervention on occupational stress reduction. Conclusions: Possible reasons for the missing effect might be the low stress level of participants or the type of the intervention delivery. Since apprenticeships in Switzerland differ considerably, future studies should enable more adapted interventions for the apprentices and consider individual circumstances of stress. Further, the intervention should focus on apprentices with high occupational stress levels or a high‐risk of stress. Studies should investigate exactly when and why a person needs support regarding her/his occupational stress. Therefore, objective measurements of stress could be helpful. [ABSTRACT FROM AUTHOR]

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The goal of a recently concluded project in Switzerland was to pioneer an assessment system for lexical signs of Swiss German Sign Language (Deutschschweizerische Gebärdensprache, DSGS) that relies on automatic sign language recognition. The assessment system gives adult L2 learners of DSGS feedback on the correctness of the manual parameters of signing (handshape, hand position, location, and movement) of isolated signs they produce. In its initial version, the system includes automatic feedback for a subset of a DSGS vocabulary size production test consisting of approximately 100 lexical items at CEFR level A1. The paper at hand reports on the process of selecting the items for the test, compiling training data for the SLR system, and linguistically analyzing errors in the resulting video recordings. [ABSTRACT FROM AUTHOR]

The use of information and communication technologies (ICTs) allows to work in multiple locations. The purpose of this article is to investigate how multilocal knowledge workers engage in work in the interplay of workplaces between cities and mountain regions. We follow a mixed methods approach with intertwined quantitative and qualitative data sources. The results show that working in the periphery using marginality can be beneficial and disadvantageous at the same time. Furthermore, marginality is seldom utilized for creativity but preferably for working undisturbed. This study contributes to the literature on marginality and flexible working between urban centers and rural peripheries in the digital age. • Multilocal knowledge workers strategically seek to work in peripheries. • Mixed methods approach identifies subtleties of work at different locations. • Using marginality for work is beneficial and disadvantageous at the same time. • Cyclical working in center and periphery increases work efficiency. • Localization of creative activities must be reconsidered due to multilocal work. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to compare the risk of complications and recurrence between oncoplastic and conventional breast surgery. Methods: This is a retrospective analysis of a consecutive series of 436 patients with stage I–III breast cancer who underwent surgery at the University Hospital of Basel between 2011 and 2018. Results: The nipple/skin-sparing mastectomy (NSM/SSM) group showed significantly more delayed wound healing (32.7 vs. 5.8%, p < 0.001) and skin necrosis (13.9 vs. 1.9%, p = 0.020) compared to conventional mastectomy (CM), which corresponded to significantly higher odds of short-term complications (OR 2.34, 95% CI 1.02–5.35, p = 0.044). The incidence rate of long-term morbidity in oncoplastic breast-conserving surgery (OBCS) was significantly higher compared to conventional breast-conserving surgery (CBCS; 25.5 vs. 11.3 per 100 patient years [PY], p < 0.001), in particular concerning chronic pain (13.3 vs. 6.6, p = 0.011) and lymphedema (4.1 vs. 0.4, p = 0.003). Seroma as a long-term morbidity occurred more often in the CM group compared to the NSM/SSM group (5.8 vs. 0.5 per 100 PY, p = 0.004). Patients received adjuvant treatment earlier after CM compared to NSM/SSM (HR 1.83, 95% CI 1.05–3.19, p = 0.034). There were no significant differences in the incidence of positive margins nor in the odds of recurrence after OBCS versus CBCS and after NSM/SSM versus CM. Conclusions: Even though the present study confirmed expected differences in complications and morbidity, it suggested that oncoplastic surgery is oncologically safe. Patients undergoing NSM/SSM should be followed closely to allow early detection and treatment of frequently associated complications and ensure timely start of adjuvant therapy. [ABSTRACT FROM AUTHOR]

Buying-shopping disorder and its transferability to the online sector is controversial. This study investigates in-store and online shopping patterns by comparing data-based modeling to a diagnostic cut-off approach. Further aims were to test model equivalence for gender and identify socio-demographic risk factors. In a representative survey, the Bergen Shopping Addiction Scale (BSAS) was applied, using both an online and in-store version. Latent class analyses were followed by multinomial logistic regression analyses to investigate socio-demographic variables. Measurement invariance across genders was tested with multi-group comparisons. With N = 1,012, 3-class solutions provided the best model fit for both in-store and online shopping. Most individuals (76, 86%) were grouped in non-addicted classes, followed by risky (21, 11%) and addicted classes (both 3%). Twenty-eight percent of individuals in the online addicted shopping class remained unidentified using the cut-off. For online shopping, only lower age and education differentiated classes significantly. Results indicate a close link between online and in-store shopping, albeit with distinguishing features. The cut-off yielded findings discrepant from class probabilities. That buying-shopping disorder mainly affects younger women of lower educational level must be questioned, given the limited associations identified. It is important not only to consider different settings of pathological shopping, but also to focus on groups that may not have appeared at risk in previous investigations (e.g., men, older age). The BSAS cut-off warrants further research. [ABSTRACT FROM AUTHOR]

This study aimed to examine associations between risk factors suggested in the pathway model proposed by Billieux et al., demographic and substance use variables, and problematic smartphone use (PSU). The analytical sample consisted of 5,096 Swiss men (mean age = 25.5 years, SD = 1.26). Multiple linear regression analyses were conducted with PSU as dependent and the following as independent variables: (a) Billieux's pathway model variables (depression, social anxiety, ADHD, aggression–hostility, and sensation seeking); (b) substance use variables [alcohol: at-risk risky single-occasion drinking (RSOD); at-risk volume drinking; tobacco use: daily smoking; illicit drug use: more than weekly cannabis use; having used at least one other illicit drug besides cannabis over the preceding 12 months]; and (c) sociodemographic variables (age, language region, and education). All pathway-model variables except sensation seeking were significant predictors of PSU, especially symptoms of social anxiety (β = 0.196) and ADHD (β = 0.184). At-risk RSOD was positively (β = 0.071) associated with PSU, whereas both frequent cannabis use (β = −0.060) and daily cigarette smoking (β = −0.035) were negatively associated with PSU. Higher-achieved educational levels and being from the German-speaking part of Switzerland predicted PSU. The findings of this study can be used to develop tailored interventional programs that address the co-occurrence of certain risky behaviors (e.g., at-risk RSOD and PSU) and target individuals who might be particularly prone to PSU. Such interventions would need to ensure that addressing one problem (e.g., decreasing PSU) does not lead to some other compensatory behavior (e.g., frequent cigarette smoking). [ABSTRACT FROM AUTHOR]

Introduction Moderators of outcome are investigated in a technology-based intervention that has been shown to effectively reduce binge drinking among adolescents. Methods Secondary data analyses were performed on socio-demographic, health-related, and socio-cognitive moderators of intervention efficacy. Students attending 80 vocational and upper secondary school classes with different levels of alcohol use were randomized to either a web- and text messaging-based intervention ( n = 547) or an assessment-only control group ( n = 494). Moderators of outcome were analysed across the entire sample, and separately for lower-risk and higher-risk drinkers. Results Based on an intention-to-treat analysis, we identified smoking status and educational level to moderate the intervention effectiveness across the total sample and in the lower-risk subsample, with a greater reduction in binge-drinking prevalence in smokers versus non-smokers, and in more highly-educated versus less-educated adolescents. Conclusions Technology-based interventions targeting heavy drinking might be especially effective in smokers and highly-educated adolescents. Interventions can prevent low-risk drinkers that smoke from developing a problematic alcohol use. [ABSTRACT FROM AUTHOR]

Background: Few studies have compared characteristics of clients entering alcohol treatment who differ in their drinking goal preferences or have investigated the relevance of drinking goals as a predictor of treatment outcomes. Objectives: To investigate associations between baseline drinking goal preferences and client characteristics as well as treatment retention and outcomes among clients in outpatient alcohol treatment. Methods: Secondary data analyses on a longitudinal multicenter study investigating the effectiveness of outpatient alcohol treatment in Switzerland among 805 clients. Assessments were conducted at treatment admission, discharge, and at 6- and 12-month follow ups. At-risk drinking was assessed through the alcohol use disorders identification test. Treatment retention was defined as regular discharge with or without transition into another institution. Results: Clients aiming to abstain from drinking were more likely to be in retreatment, to be assigned to treatment by a health institution, to have no at-risk alcohol use, and to be already alcohol abstinent at the time of admission relative to clients who aimed to control their drinking. Clients without at-risk alcohol use at admission showed higher treatment retention when aiming for controlled drinking than for abstinence, while there was no difference in treatment retention among clients with at-risk use. Clients with at-risk use at admission were more likely to reach not-at-risk alcohol use status when aiming for alcohol abstinence than for controlled drinking. Conclusions: Drinking goals are associated with variables of alcohol use and treatment assignment. They have different effects on treatment retention and treatment outcomes according to alcohol use at the time of admission. [ABSTRACT FROM AUTHOR]

Background: Few studies have reported on the outcomes of outpatient alcohol treatment or the factors associated with effective treatment. We investigated treatment outcome, treatment retention, and their predictors in clients receiving outpatient treatment for alcohol misuse.Methods: Naturalistic, longitudinal multi-centre study in Switzerland that included 858 clients receiving outpatient treatment for alcohol misuse. Assessments were conducted at treatment admission, discharge, and 6- and 12-month follow-ups. Non-problem drinking was used as an indicator of positive treatment outcome.Results: Clients admitted to outpatient alcohol treatment were highly heterogeneous in terms of pre-treatment alcohol use and drinking goals. 45 % of clients exhibiting problem drinking at the beginning of treatment showed non-problem drinking at discharge, and 41 % and 43 % showed non-problem drinking at the 6- and 12-month follow-up, respectively; 51 % were discharged regularly and 43 % were discharged irregularly. Non-problem drinking at the 12-month follow-up was more likely in clients with a higher life satisfaction, those with lower alcohol use, those aiming for alcohol abstinence, and those who had been admitted for the first time to a treatment institution, whereas it was less likely in clients with a higher educational level. Treatment retention was higher among older clients, clients with a higher life satisfaction, and clients who subsisted on their own income.Conclusion: Irregular discharge is high in outpatient alcohol treatment; nevertheless, a substantial portion of clients can achieve and maintain non-problem drinking by a 12-month follow-up. [ABSTRACT FROM AUTHOR]

Aims To estimate the prevalence of self-reported pharmacological neuroenhancement (PNE) with prescription or recreational drugs among the Swiss general population and correlates of PNE. Design A population-based cross-sectional study using a self-administered online survey. Setting A telephone-recruited highly representative internet panel in Switzerland. Participants A total of 10 171 Swiss employees and students (unweighted n = 10 084) aged 15-74 years (mean age: 39.1 ± 13.3; 46.6% female). Measurements Self-reported life-time, past-year and past-month use of prescription or recreational drugs for PNE, motives for use and correlates of PNE, including socio-demographic, health and recreational drug use characteristics. Findings The life-time prevalence of PNE was 4.0% [95% confidence interval (CI) = 3.62, 4.38], and the past-year prevalence was 2.1% (95% CI = 1.82, 2.38). Life-time pharmacological mood enhancement (3.1%; 95% CI = 2.76, 3.44) was more prevalent than pharmacological cognitive enhancement (1.4%; 95% CI = 1.17, 1.63). Fifty-four participants reported both (0.5%; 95% CI = 0.36, 0.64). PNE was associated with studying rather than full-time [odds ratio (OR) = 0.35; 95% CI = 0.21, 0.57] or part-time employment (OR = 0.39; 95% CI = 0.23, 0.67), stress (OR = 1.51 95% CI = 1.31, 1.75), cocaine (OR = 2.40; 95% CI = 1.51, 3.82) and amphetamine use (OR = 2.44; CI 95% = 1.37, 4.33), diagnosis of a mental disorder (OR = 4.26; 95% CI = 3.14, 5.80), and perceived poor health (OR = 0.76; 95% CI = 0.64, 0.90). Conclusions Taking prescription or recreational drugs for pharmacological neuroenhancement is rare among Swiss employees and students (4.0%). Pharmacological mood enhancement (3.1%) is more prevalent than direct pharmacological cognitive enhancement (1.4%). [ABSTRACT FROM AUTHOR]

Objectives: This study examined the relationship between stress, self-efficacy, self-medication, and pharmacological neuroenhancement (PNE) in the Swiss general population.Methods: Using the largest Swiss Internet panel, a sample of 10,171 employees and students (unweighted N=10,084) aged 15-74 years was recruited and asked to complete a self-administered online survey. The data were weighted for age, sex, and language region to provide results that were representative of the Swiss population. Multinomial logistic regression models were conducted to identify predictors of pharmacological cognitive enhancement (PCE) and pharmacological mood enhancement (PME) over the past year. Two self-medication models and an overall model were determined.Results: Current medical treatment for a mental disorder was the best predictor of both PCE and PME use as serious self-medication. The overall model revealed that cannabis use, frequent stress, and long-term stress were predictors of both PCE and PME, whereas negative stressors and time pressure at work did not remain in the final model. Furthermore, past-year PCE with and without PME was associated with being male, being a student, and using illegal drugs other than cannabis, whereas being female and having low self-efficacy predicted past-year PME only.Conclusions: Consideration of the predictor variables identified in this study may help to identify the potential PCE and PME users for whom measures to prevent drug abuse and manage stress are most appropriate. More specifically, the use of PCE and PME as self-medication to enhance performance at work or while studying needs further consideration in the neuroenhancement debate. [ABSTRACT FROM AUTHOR]

Aims: To test the feasibility, acceptability and initial effectiveness of a text message-based aftercare treatment programme among alcohol outpatients. Methods: Clients treated for alcohol use disorders from three Swiss outpatient alcohol treatment centres were invited by their counsellors to participate in a study testing an interactive aftercare programme employing the use of text messages and personal phone calls. Fifty study participants were randomly assigned to either the 6-month aftercare programme (n = 25) or treatment as usual (n = 25). The intervention consisted of (a) monitoring of self-selected drinking goals at regular intervals, (b) motivational text messages to stick to self-selected drinking goals and (c) proactive telephone calls from counsellors when participants neglected to stick to their drinking goals or expressed a need for support. Follow-up interviews were conducted 6 months after randomization. Results: Throughout the programme, participants received a total of 421 text message prompts. Out of these, participants provided valid replies to 371 (88.1%) within 48 h. Out of the 25 participants in the intervention group, 11 (44.0%) sent at least one call-for-help reply. Based on complete case data, at risk alcohol use at follow-up was 41.7% in the control group and 28.6% in the intervention group (OR = 0.56, 95% CI = 0.16–1.95, P = 0.36). Conclusions: The interactive low-intensive aftercare programme was well accepted by the participants. Testing its efficacy within an adequately powered randomized controlled trial might be reasonable. [ABSTRACT FROM PUBLISHER]

Severe floods triggered by intense precipitation are among the most destructive natural hazards in Alpine environments, frequently causing large financial and societal damage. Potential enhanced flood occurrence due to global climate change would thus increase threat to settlements, infrastructure, and human lives in the affected regions. Yet, projections of intense precipitation exhibit major uncertainties and robust reconstructions of Alpine floods are limited to the instrumental and historical period. Here we present a 2500-year long flood reconstruction for the European Alps, based on dated sedimentary flood deposits from ten lakes in Switzerland. We show that periods with high flood frequency coincide with cool summer temperatures. This wet-cold synchronism suggests enhanced flood occurrence to be triggered by latitudinal shifts of Atlantic and Mediterranean storm tracks. This paleoclimatic perspective reveals natural analogues for varying climate conditions, and thus can contribute to a better understanding and improved projections of weather extremes under climate change. [ABSTRACT FROM AUTHOR]

Background: Tobacco smoking, hazardous drinking and physical inactivity during adolescence are risk factors that are associated with poorer health in adulthood. The identification of subgroups of young people with a high prevalence of one or more of these risk factors allows an optimised allocation of preventive measures. This study aimed at investigating hazardous drinking, tobacco smoking and physical inactivity as well as their associations and demographic predictors in vocational school students. Methods: Out of 57 contacted vocational schools in Switzerland, a total of 24 schools participated in a survey assessing gender, age, immigrant background, educational attainment and vocational field as well as the above mentioned health risk factors. Out of the 2659 students present in 177 included vocational school classes, 2647 (99.5%) completed the survey. Binary logistic regression analyses were conducted to investigate the demographic predictors of each health risk factor and a multinomial logistic regression analysis was conducted to investigate predictors of different risk factor combinations. Results: Of the surveyed students, 79.4% showed at least one risk factor, 43.6% showed two or more and 9.6% showed all three health risk factors. Hazardous drinking was more prevalent in male, physical inactivity was more prevalent in female vocational school students. The proportion of students with low physical activity and tobacco smoking increased with increasing age. While the combination of hazardous drinking and tobacco smoking was higher in males, the other risk factor combinations were observed particularly among females. Conclusions: Multiple risk factors were ascertained in a significant proportion of vocational school students. Specifically, tobacco smoking and hazardous drinking were coexistent. The study underlines the need for preventive measures in specific subpopulations of adolescents and young adults with lower educational level. [ABSTRACT FROM AUTHOR]

Abstract: A comprehensive R&D program on LAr Time Projection Chambers (LAr TPC) is presently being carried out at the University of Bern. Many aspects of this technology are under investigation: HV, purity, calibration, readout, etc. Furthermore, multi-photon interaction of UV-laser beams with LAr has successfully been measured. Possible applications of the LAr TPC technology in the field of homeland security are also being studied. In this paper, the main aspects of the program will be reviewed and the achievements underlined. Emphasis will be given to the largest device in Bern, i.e. the 5 m long ARGONTUBE TPC, meant to prove the feasibility of very long drifts in view of future large scale applications of the technique. [Copyright &y& Elsevier]

Background: Subcutaneous allergen-specific immunotherapy is an effective treatment of IgE-mediated allergies, but it requires repeated allergen injections with a risk of systemic allergic reactions. Transcutaneous immunotherapy may improve patient compliance and safety. Objective: To assess the safety and efficacy of epicutaneous allergen immunotherapy. Methods: This monocentric, placebo-controlled, double-blind trial was conducted from March 2006 to December 2007 at the University Hospital Zurich. Thirty-seven adult patients with positive skin prick and nasal provocation tests to grass pollen were randomized to receive patches containing either allergen (n = 21) or placebo (n = 16). Treatment took place before and during the pollen season 2006, and follow-up visits took place before (n = 26) and after the pollen season 2007 (n = 30). The primary outcome measures were nasal provocation tests. Results: Allergen-treated patients showed significantly decreased scores in nasal provocation tests in the first (P < .001) and second year (P = .003) after treatment. In contrast, placebo-treated patients had decreased scores in the first treatment year, 2006 (P = .03), but the effect diminished in the second year (P = .53). Although improvement of nasal provocation test scores was not significantly better in the verum versus placebo group, the overall treatment success was rated significantly higher by the allergen-treated group than by the placebo group (2006, P = .02; 2007, P = .005). No severe adverse events were observed. Occurrence of eczema after allergen patch applications proved stimulation of specific T-cell responses, but was noted as an adverse effect of the treatment. Conclusion: Epicutaneous allergen immunotherapy is a promising strategy to treat allergies and merits further investigation. [Copyright &y& Elsevier]

Scand J Caring Sci; 2005; 19; 296–300 The Impact of Patient Aggression on Carers Scale: instrument derivation and psychometric testing Patient aggression towards carers constitutes a problem for patients and carers alike. Patients’ aggressive behaviour often leads to adverse consequences for carers, especially nurses. Various extensive instruments have been developed to measure such adverse effects on carers. The ‘Impact of Patient Aggression on Carers Scale’ (IMPACS) is a short instrument intended for use in monitoring negative consequences of such incidents. The items of the IMPACS were derived basically from a review of the literature on negative effects of patient aggression on nurses. The IMPACS was administered to a convenience sample of nurses working on 14 psychiatric acute admission wards in the German speaking part of Switzerland. Factor analysis led to the exclusion of three of the original items and to an interpretable three-factor solution with all factors demonstrating eigen values higher than 1. The factors demonstrate moderate to good internal consistency. Canonical correlation analysis using the dimensions of the Maslach Burnout Inventory (MBI) produced a correlation coefficient of 0.457, thus demonstrating external reliability. In spite of some caveats such as possible response bias and the necessity of the investigation of the test–retest stability of the scale this study suggests that the IMPACS is a good measure of adverse effects and thus merits further development. [ABSTRACT FROM AUTHOR]

The development of medicinal products often continues throughout the different phases of a clinical study and may require challenging changes in raw and starting materials at later stages. Comparability between the product properties pre- and post-change thus needs to be ensured. Here, we describe and validate the regulatory compliant change of a raw material using the example of a nasal chondrocyte tissue-engineered cartilage (N-TEC) product, initially developed for treatment of confined knee cartilage lesions. Scaling up the size of N-TEC as required for the treatment of larger osteoarthritis defects required the substitution of autologous serum with a clinical-grade human platelet lysate (hPL) to achieve greater cell numbers necessary for the manufacturing of larger size grafts. A risk-based approach was performed to fulfill regulatory requirements and demonstrate comparability of the products manufactured with the standard process (autologous serum) already applied in clinical indications and the modified process (hPL). Critical attributes with regard to quality, purity, efficacy, safety and stability of the product as well as associated test methods and acceptance criteria were defined. Results showed that hPL added during the expansion phase of nasal chondrocytes enhances proliferation rate, population doublings and cell numbers at passage 2 without promoting the overgrowth of potentially contaminant perichondrial cells. N-TEC generated with the modified versus standard process contained similar content of DNA and cartilaginous matrix proteins with even greater expression levels of chondrogenic genes. The increased risk for tumorigenicity potentially associated with the use of hPL was assessed through karyotyping of chondrocytes at passage 4, revealing no chromosomal changes. Moreover, the shelf-life of N-TEC established for the standard process could be confirmed with the modified process. In conclusion, we demonstrated the introduction of hPL in the manufacturing process of a tissue engineered product, already used in a late-stage clinical trial. Based on this study, the national competent authorities in Switzerland and Germany accepted the modified process which is now applied for ongoing clinical tests of N-TEC. The described activities can thus be taken as a paradigm for successful and regulatory compliant demonstration of comparability in advanced therapy medicinal products manufacturing. [ABSTRACT FROM AUTHOR]

Background: Articular cartilage injuries have poor repair capacity, leading to progressive joint damage, and cannot be restored predictably by either conventional treatments or advanced therapies based on implantation of articular chondrocytes. Compared with articular chondrocytes, chondrocytes derived from the nasal septum have superior and more reproducible capacity to generate hyaline-like cartilage tissues, with the plasticity to adapt to a joint environment. We aimed to assess whether engineered autologous nasal chondrocyte-based cartilage grafts allow safe and functional restoration of knee cartilage defects.Methods: In a first-in-human trial, ten patients with symptomatic, post-traumatic, full-thickness cartilage lesions (2-6 cm(2)) on the femoral condyle or trochlea were treated at University Hospital Basel in Switzerland. Chondrocytes isolated from a 6 mm nasal septum biopsy specimen were expanded and cultured onto collagen membranes to engineer cartilage grafts (30 × 40 × 2 mm). The engineered tissues were implanted into the femoral defects via mini-arthrotomy and assessed up to 24 months after surgery. Primary outcomes were feasibility and safety of the procedure. Secondary outcomes included self-assessed clinical scores and MRI-based estimation of morphological and compositional quality of the repair tissue. This study is registered with ClinicalTrials.gov, number NCT01605201. The study is ongoing, with an approved extension to 25 patients.Findings: For every patient, it was feasible to manufacture cartilaginous grafts with nasal chondrocytes embedded in an extracellular matrix rich in glycosaminoglycan and type II collagen. Engineered tissues were stable through handling with forceps and could be secured in the injured joints. No adverse reactions were recorded and self-assessed clinical scores for pain, knee function, and quality of life were improved significantly from before surgery to 24 months after surgery. Radiological assessments indicated variable degrees of defect filling and development of repair tissue approaching the composition of native cartilage.Interpretation: Hyaline-like cartilage tissues, engineered from autologous nasal chondrocytes, can be used clinically for repair of articular cartilage defects in the knee. Future studies are warranted to assess efficacy in large controlled trials and to investigate an extension of indications to early degenerative states or to other joints.Funding: Deutsche Arthrose-Hilfe. [ABSTRACT FROM AUTHOR]