A Fully Automated Pulsating Support System for Pressure Injury Prevention and Treatment in 10 Belgium Nursing Homes: An Observational Study.

PURPOSE: We studied pressure injury (PI) stage II-IV cumulative incidence and the change of PI status in the sacral area of nursing home residents associated with the use of a fully automated pulsating support system air mattress in use for 30 days. We also assessed caregivers', residents', and their family members' experiences and perceptions of mattress comfort and other factors such as pain. DESIGN: Multicenter cohort study. SUBJECT AND SETTING: A convenience sample of 40 residents residing in 10 Belgian nursing homes was recruited. METHODS: Pressure injury classification was confirmed using the European Pressure Ulcer Advisory Panel classification system. The Pressure Ulcer Scale for Healing (PUSH) tool was used to assess and measure PI status change. A comfort assessment was performed at end of the study. Cumulative PI incidence of stages II-IV was calculated, and frequencies and percentages were used to describe the results of the comfort assessments. RESULTS: Residents were allocated to the prevention group (n = 22) and to the treatment group (n = 18). The cumulative PI incidence was 4.5% (n = 1/22) in the prevention group. In the treatment group, the mean score on the PUSH tool decreased from 9.36 to 7.70 during the observation period, indicating an overall improvement. Four of the existing PIs healed, 17 PIs remained stable, and 1 PI deteriorated. The comfort questionnaires were completed by 76 nursing home caregivers, 21 family members, and 11 residents in the 10 participating nursing homes; the mattress comfort was perceived as very good, and pain was noted to decrease. CONCLUSIONS: Low cumulative PI incidence findings were observed with use of the mattress for the prevention of PIs and resulted in improvements in existing PIs, results which are consistent with several existing studies. The majority of the caregivers, residents, and family members evaluated the mattress as comfortable. Future research is needed to corroborate findings in larger randomized clinical trials.

Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues: A scoping review.

Deep tissue injuries are pressure ulcers which initiate in the subcutaneous tissues and extend through a bottom-up pathway. Once deep tissue injuries are visual at skin level, serious irreversible tissue damage has already occurred. In pressure ulcer development, inflammation and edema are coupled physiological processes associated with tissue damage arising due to sustained mechanical loading. This study aimed to provide an in-depth overview of the physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues, in the context of pressure ulceration. A scoping review was performed according to the framework by Arksey and O'Malley. The databases MEDLINE, EMBASE, Web of Science, and Scopus, and the reference lists of included studies were searched for in vivo (animal, human), and in vitro studies matching the study objectives (from inception to 28 May 2018). No restrictions for inclusion were applied for study design, setting, participants, and year of publication. A total of 12 studies were included, varying in study design, sample characteristics, amount and duration of mechanical loads that were applied, follow-up time, and assessment methods. Neutrophil infiltration and edema occur in the subcutaneous tissues nearly immediately after the application of load on soft tissues. The amount of neutrophils and edema increase in the first days after the mechanical insult and decrease once healing has been initiated and no supplementary mechanical load was applied. One study indicated that edema may extend up to the level of the dermo-epidermal junction. Further research should focus on how deep tissue inflammation and edema are reflected into unique tissue changes at skin level, and how abnormal inflammatory responses manifest (e.g. when the nervous system is not functioning normally).

Modifiable patient-related factors associated with pressure ulcers on the sacrum and heels: Secondary data analyses.

AIM: To explore factors associated with the presence of category I-IV pressure ulcers on the sacrum and heels. DESIGN: Cross-sectional, secondary data analysis using data collected from the Landelijke Prevalentiemeting Zorgproblemen (LPZ) project, a multicentre prevalence study including nursing home residents and community care clients (N = 4,842) in the Netherlands in 2017. METHODS: A single binary logistic regression model was designed to identify factors associated with the presence of pressure ulcers. Additionally, a multiple binary logistic regression model including modifiable explanatory factors associated with the presence of pressure ulcers was designed. RESULTS: Impaired mobility, friction and shear (evaluated using the Braden Scale) are significantly associated with the presence of both sacral and heel category I-IV pressure ulcers. Incontinence-associated dermatitis is significantly associated with category I-IV sacral pressure ulcers. CONCLUSION: In pressure ulcer prevention, nursing interventions should focus on frequent repositioning and mobilization while avoiding exposure of the skin to friction and shear. The need to consider incontinence-associated dermatitis, incontinence and moisture as important factors in pressure ulcer risk assessment is confirmed. IMPACT: Pressure ulcers occur when skin and tissues are deformed between bony prominences and the support surface in a sitting or lying position. They are the result of a complex interaction between direct causal factors and a wide range of indirect factors. Recognition of these factors influences risk assessment guidance and practice. Knowledge of skin-specific factors at the patient level, modifiable by nursing interventions, enables a better targeted and tailored preventive approach.

Outcome measurement instruments for erythema associated with incontinence-associated dermatitis: Systematic review.

AIM: To: (a) examine which outcome measurement instruments for erythema associated with incontinence-associated dermatitis (IAD) with supporting evidence about measurement properties are available; (b) evaluate the methodological quality of the studies and the quality of the measurement properties; and (c) identify eligible instruments to measure erythema in incontinence-associated dermatitis research. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, CINAHL and CENTRAL were systematically searched until July 2018 (update December 2018). Additional input was gathered from 151 incontinence-associated dermatitis experts. Cited and citing references of included studies were screened. REVIEW METHODS: The COSMIN Risk of Bias checklist was applied to evaluate the methodological quality of the studies. Reported measurement properties were rated against criteria for good measurement properties. RESULTS: Fourteen studies, describing 10 measurement instruments, were included. In five instruments, erythema was captured as a separate concept, two studies provided empirical evidence about the measurement properties. The most studied measurement properties were reliability (9 studies), measurement error (4 studies) and criterion validity (4 studies). In one study, internal consistency was examined. CONCLUSION: No instrument measuring exclusively erythema associated with incontinence-associated dermatitis exists. There is no single composite incontinence-associated dermatitis measurement instrument that outperforms others. Development or adaption of an instrument to measure erythema associated with incontinence-associated dermatitis is one option to solve this challenge. IMPACT: The evidence about measurement properties of instruments measuring erythema associated with incontinence-associated dermatitis has not been summarized to date. The lack of an instrument should trigger activities to measure this domain accurately in future clinical trials.

The prevalence and associated factors of skin tears in Belgian nursing homes: A cross-sectional observational study.

BACKGROUND: Although skin tears are among the most prevalent acute wounds in nursing homes, their recognition as a unique condition remains in its infancy. Elderly patients are at risk of developing skin tears due to increased skin fragility and other contributing risk factors. In order to provide (cost-) effective prevention, patients at risk should be identified in a timely manner. OBJECTIVES: (1) To determine the point prevalence of skin tears and (2) to identify factors independently associated with skin tear presence in nursing home residents. METHODS: A cross-sectional observational study was set up, including 1153 residents in 10 Belgian nursing homes. Data were collected by trained researchers and study nurses using patient records and skin observations. A multiple binary logistic regression model was designed to explore independent associated factors (significance level α < 0.05). RESULTS: The final sample consisted of 795 nursing home residents, of which 24 presented with skin tears, resulting in a point prevalence of 3.0%. Most skin tears were classified as category 3 (defined as complete flap loss) according to the International Skin Tear Advisory Panel (ISTAP) Classification System and 75.0% were located on the lower arms/legs. Five independent associated factors were identified: age, history of skin tears, chronic use of corticosteroids, dependency for transfers, and use of adhesives/dressings. CONCLUSIONS: This study revealed a skin tear prevalence of 3.0% in nursing home residents. Age, history of skin tears, chronic use of corticosteroids, dependency for transfers, and use of adhesives/dressings were independently associated with skin tear presence.

Design and psychometric testing of the attitude towards the prevention of incontinence-associated dermatitis instrument (APrIAD).

Despite the availability of a range of skin care products for the prevention of incontinence-associated dermatitis (IAD), prevalence remains high. Nurses' attitude is an important determinant to take into account in quality improvement projects. This study aimed to design a psychometrically test the attitude towards the prevention of incontinence-associated dermatitis instrument (APrIAD). A prospective psychometric instrument validation study was performed in a convenience sample of 217 Belgian nurses. Construct validity and reliability (internal consistency, stability) were tested. The exploratory factor analysis demonstrated a model consisting of four factors and 14 items: (a) beliefs about the impact of IAD on patients, (b) beliefs about team responsibility to prevent IAD, (c) beliefs about personal responsibility to prevent IAD, and (d) beliefs about the effectiveness of IAD prevention products and procedures. Cronbach's α was 0.72 for factor 1, 0.65 for factor 2, 0.63 for factor 3, and 0.47 for factor 4. The intra-class correlation coefficient was 0.689 (95% confidence interval [CI] 0.477-0.825) for the total instrument, 0.591 (95% CI 0.388-0.764) for factor 1, 0.387 (95% CI 0.080-0.626) for factor 2, 0.640 (95% CI 0.406-0.795) for factor 3, and 0.768 (95% CI 0.597-0.872) for factor 4. Psychometric testing of the APrIAD demonstrated adequate validity and reliability measures.

Comparison of Two Methods for Estimating the Tip Position of a Nasogastric Feeding Tube: A Randomized Controlled Trial.

BACKGROUND: Several studies have shown that the nose-earlobe-xiphoid distance (NEX) is inadequate to estimate the insertion length of nasogastric tubes. An alternative approach tested in these studies, which leads to > 90% well-placed nasogastric tubes, used a corrected calculation of the NEX: (NEX × 0.38696) + 30.37. The primary aim of this study was to determine whether using the corrected NEX was more successful than the NEX in determining the insertion length. The secondary aim was to investigate the likelihood to successfully obtain gastric aspirate. METHODS: Adult patients in a general hospital (N = 215) needing a nasogastric tube were randomized to the control (NEX) or intervention group (corrected NEX). Tip positioning was verified using X-ray. Correct tip positioning was defined as between 3 and 10 cm under the lower esophageal sphincter (LES). RESULTS: In >20% of all patients, both methods underestimated the required tube length for correct positioning. The NEX showed an overestimation (17.2%) of the insertion length (>10 cm under the LES) compared with the corrected NEX (4.8%). There was no difference (P = 0.938) between the 2 groups in obtaining gastric aspirate (55.6% vs 56%). However, correct tip positioning resulted in a fourfold increase of obtaining gastric aspirate. CONCLUSIONS: Both methods resulted in a high risk of incorrectly placed tubes due to malposition of the tip near the LES or distal esophagus. This may increase the risk of reflux and pulmonary aspiration. Based on these results, the development of more reliable methods requires consideration.

Core outcome domains in incontinence-associated dermatitis research.

AIM: To report the development of a core set of outcome domains for clinical research involving adults with incontinence-associated dermatitis or at risk, independently from any geographical location or skin colour. BACKGROUND: The management of incontinence-associated dermatitis is important in caring for incontinent patients. The lack of comparability of clinical trial outcomes is a major challenge in the field of evidence-based incontinence-associated dermatitis prevention and treatment. Core outcome sets may therefore be helpful to improve the value of clinical incontinence-associated dermatitis research. DESIGN: Systematic literature review, patient interviews and consensus study using Delphi procedure. METHODS: A list of outcome domains was generated through a systematic literature review (no date restrictions-April 2016), consultation of an international steering committee and three patient interviews. The project team reviewed and refined the outcome domains prior to starting a three-round Delphi procedure conducted between April-September 2017. The panellists, including healthcare providers, researchers and industry were invited to rate the importance of the outcome domains. RESULTS: We extracted 1,852 outcomes from 244 articles. Experts proposed 56 and patients 32 outcome domains. After refinement, 57 panellists from 17 countries rated a list of 58 outcome domains. The final list of outcome domains includes erythema, erosion, maceration, IAD-related pain and patient satisfaction. CONCLUSION: Erythema, erosion, maceration, incontinence-associated dermatitis -related pain and patient satisfaction are the most important outcome domains to be measured in incontinence-associated dermatitis trials. Based on this international consensus on what to measure, the question of how to measure these domains now requires consideration. Registration: This project has been registered in the Core Outcome Measures in Effectiveness Trials (COMET Initiative) database and is part of the Cochrane Skin Group-Core Outcomes Set Initiative (CSG-COUSIN).

Independent risk factors for the development of incontinence-associated dermatitis (category 2) in critically ill patients with fecal incontinence: A cross-sectional observational study in 48 ICU units.

BACKGROUND: Critically ill patients suffering from fecal incontinence have a major risk of developing incontinence-associated dermatitis (IAD). The presence of moisture and digestive enzymes (lipase, protease) negatively influences skin barrier function. Additional risk factors will make some patients even more vulnerable than others. In order to provide (cost) effective prevention, this specific patient population should be identified timely. OBJECTIVES: To identify independent risk factors for the development of IAD category 2 (skin loss) in critically ill patients with fecal incontinence. DESIGN: A cross-sectional observational study. SETTING AND PARTICIPANTS: The study was performed in 48 ICU wards from 27 Belgian hospitals. Patients of 18 years or older, with fecal incontinence at the moment of data collection, were eligible to participate. Patients with persistent skin redness due to incontinence (IAD category 1) were excluded. METHODS: Potential risk factors were carefully determined based on literature and expert consultations. Data were collected over a period of eight months by trained researchers using patient records and observation of skin care practices. At the time a patient was included in the study, all relevant data from the past six days, or since admission at the ICU, were recorded. Simultaneously, direct skin observations were performed and high definition photographs were ratified by an expert IAD researcher. A multiple binary logistic regression model was composed to identify independent risk factors. Variables with P < .25 in single binary logistic regression analyses were added to the multiple model using a forward procedure. A cut-off value of P < .1 was established to retain variables in the final model. Nagelkerke's R2 and Hosmer-Lemeshow statistic were calculated as measures of model fit. RESULTS: The sample comprised of 206 patients, of which 95 presented with IAD category 2, and 111 were free of IAD. Seven independent risk factors were identified: liquid stool [odds ratio (OR) 4.69; 95% confidence interval (CI) 2.28-9.62], diabetes (OR 2.89; 95% CI 1.34-6.27), age (OR 1.05; 95% CI 1.02-1.08), smoking (OR 2.67; 95% CI 1.21-5.91), non-use of diapers (OR 2.97; 95% CI 1.39-6.33), fever (OR 2.60; 95% CI 1.23-5.53), and low oxygen saturation (OR 2.15; 95% CI 1.03-4.48). Nagelkerke's R2 was 0.377. The Hosmer-Lemeshow statistic indicated no significant difference between the observed and expected values (p = .301). CONCLUSIONS: Liquid stool, diabetes, age, smoking, non-use of diapers, fever, and low oxygen saturation were independently associated with IAD category 2 in critically ill patients with fecal incontinence.

Incontinence-Associated Dermatitis: Pathogenesis, Contributing Factors, Prevention and Management Options.

Incontinence-associated dermatitis (IAD) is a common type of irritant contact dermatitis, seen in patients with urinary or faecal incontinence. Mechanical factors such as traumata and friction may aggravate the lesions. The fragile skin in elderly patients is more prone to developing IAD. The clinical picture of IAD consists of persistent redness on the one hand and skin loss on the other. Both categories may be associated with clinical signs of major colonisation or infection. It is important to distinguish IAD from pressure ulcers and other dermatoses in the genital region. Due to the lack of well-established clinical trials, recommendations about prevention and treatment are based on expert opinion and best practice. Gentle cleansing, use of hydrating topical agents and application of barrier products are the main elements in the prevention and treatment of IAD. It is important to translate these recommendations and general guidelines into ready-to-use protocols that can be implemented for each specific clinical manifestation of IAD.

Development and psychometric validation of PUKAT 2·0, a knowledge assessment tool for pressure ulcer prevention.

The aim of this study was to develop a tool to measure the knowledge of nurses on pressure ulcer prevention. PUKAT 2·0 is a revised and updated version of the Pressure Ulcer Knowledge Assessment Tool (PUKAT) developed in 2010 at Ghent University, Belgium. The updated version was developed using state-of-the-art techniques to establish evidence concerning validity and reliability. Face and content validity were determined through a Delphi procedure including both experts from the European Pressure Ulcer Advisory Panel (EPUAP) and the National Pressure Ulcer Advisory Panel (NPUAP) (n = 15). A subsequent psychometric evaluation of 342 nurses and nursing students evaluated the item difficulty, discriminating power and quality of the response alternatives. Furthermore, construct validity was established through a test-retest procedure and the known-groups technique. The content validity was good and the difficulty level moderate. The discernment was found to be excellent: all groups with a (theoretically expected) higher level of expertise had a significantly higher score than the groups with a (theoretically expected) lower level of expertise. The stability of the tool is sufficient (Intraclass Correlation Coefficient = 0·69). The PUKAT 2·0 demonstrated good psychometric properties and can be used and disseminated internationally to assess knowledge about pressure ulcer prevention.

CONSIDER - Core Outcome Set in IAD Research: study protocol for establishing a core set of outcomes and measurements in incontinence-associated dermatitis research.

AIM: This study protocol describes the methodology for the development of a core set of outcomes and a core set of measurements for incontinence-associated dermatitis. BACKGROUND: Incontinence is a widespread disorder with an important impact on quality of life. One of the most common complications is incontinence-associated dermatitis, resulting from chemical and physical irritation of the skin barrier, triggering inflammation and skin damage. Managing incontinence-associated dermatitis is an important challenge for nurses. Several interventions have been assessed in clinical trials, but heterogeneity in study outcomes complicates the comparability and standardization. To overcome this challenge, the development of a core outcome set, a minimum set of outcomes and measurements to be assessed in clinical research, is needed. DESIGN: A project team, International Steering Committee and panelists will be involved to guide the development of the core outcome set. The framework of the Harmonizing Outcomes Measures for Eczema roadmap endorsed by Cochrane Skin Group Core Outcomes Set Initiative, is used to inform the project design. METHODS: A systematic literature review, interviews to integrate the patients' perspective and a consensus study with healthcare researchers and providers using the Delphi procedure will be performed. The project was approved by the Ethics review Committee (April 2016). DISCUSSION: This is the first project that will identify a core outcome set of outcomes and measurements for incontinence-associated dermatitis research. A core outcome set will reduce possible reporting bias, allow results comparisons and statistical pooling across trials and strengthen evidence-based practice and decision-making. REGISTRATION: This project has been registered in the Core Outcome Measures in Effectiveness Trials (COMET) database and is part of the Cochrane Skin Group Core Outcomes Set Initiative (CSG-COUSIN).

PROTECT - trial: a multicentre prospective pragmatic RCT and health economic analysis of the effect of tailored repositioning to prevent pressure ulcers - study protocol.

AIM: The aims of this trial were as follows: (1) to compare the (cost-) effectiveness of a turning and repositioning system and an algorithm for a tailored repositioning vs. usual care to improve reposition frequency in patients at risk; and (2) to compare the (cost-) effectiveness of standardized incontinence care vs. usual care. BACKGROUND: Pressure ulcers are a serious and common problem for hospitalized patients. In many countries, pressure ulcers are recognized as a national health issue and governments designate pressure ulcers as one of the most important sentinel events for health care. International guidelines recommend the use of pressure redistributing support surfaces, systematic patient repositioning and preventive skin care to prevent pressure ulcers. Interventions should be patient-tailored and based on a thorough assessment of both the patient and contextual risk factors. There is a lack of rigorous research addressing the effectiveness of a turning and repositioning system and it is unclear how to tailor the frequency and posture to specific patient needs. DESIGN: Multicentre, cluster, three-arm, randomized, controlled pragmatic trial and a cost-effectiveness analysis. The ward is the unit of randomization. METHODS: Tailored repositioning, the use of a device to facilitate patient repositioning and an optimal procedure for incontinence care will be combined. Participating wards will be intensive care units, geriatric and rehabilitation wards. A sample size calculation was performed (80% power, α = 0·05). This study is approved by the Ethics Committee (February 2016). DISCUSSION: Data collection is currently ongoing. The results are expected to be obtained in March 2017.

Independent risk factors for the development of skin erosion due to incontinence (incontinence-associated dermatitis category 2) in nursing home residents: results from a multivariate binary regression analysis.

The aim of this study was to identify characteristics independently associated with a higher risk of developing skin damage because of incontinence [incontinence-associated dermatitis (IAD) category 2] in nursing home residents. As part of a larger randomised controlled trial, IAD incidence was monitored for 1 month in a sample of 381 incontinent residents using a validated IAD Severity Categorisation Tool. Data on demographical, physical, functional and psychological characteristics were collected. The overall IAD incidence (category 1-2) was 30·0%, and 6% of the participants developed skin damage (IAD category 2). Residents who developed IAD category 2 were less mobile [odds ratio (OR) 2·72, 95% confidence interval (CI) 1·06-6·94], had more friction and shear issues (OR 2·54; 95% CI 1·02-6·33) and had more erythema due to incontinence (OR 3·02; 95% CI 1·04-8·73) before IAD category 2 occurrence. Care providers should give full attention to risk factors to both detect residents at risk for IAD development and to start prevention in time.

Interventions for preventing and treating incontinence-associated dermatitis in adults.

BACKGROUND: Incontinence-associated dermatitis (IAD) is one of the most common skin problems in adults who are incontinent for urine, stool, or both. In practice, products and procedures are the same for both prevention and treatment of IAD. OBJECTIVES: The objective of this review was to assess the effectiveness of various products and procedures to preventand treat incontinence-associated dermatitis in adults. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, CINAHL, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 28 September 2016). Additionally we searched other electronic databases: CENTRAL(2015, Issue 4), MEDLINE (January 1946 to May Week 3 2015), MEDLINE In-Process (inception to 26 May 2015), CINAHL(December 1981 to 28 May 2015), Web of Science (WoS; inception to 28 May 2015) and handsearched conference proceedings (to June 2015) and the reference lists of relevant articles, and contacted authors and experts in the field. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) and quasi-RCTs, performed in any healthcare setting, with included participants over 18 years of age, with or without IAD. We included trials comparing the (cost) effectiveness of topical skin care products such as skin cleansers, moisturisers, and skin protectants of different compositions and skin care procedures aiming to prevent and treat IAD. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts and full-texts, extracted data, and assessed the risk of bias of the included trials. MAIN RESULTS: We included 13 trials with 1295 participants in a qualitative synthesis. Participants were incontinent for urine, stool, or both, and were residents in a nursing home or were hospitalised.Eleven trials had a small sample size and short follow-up periods. .The overall risk of bias in the included studies was high. The data were not suitable for meta-analysis due to heterogeneity in participant population, skin care products, skin care procedures, outcomes, and measurement tools.Nine trials compared different topical skin care products, including a combination of products. Two trials tested a structured skin care procedure. One trial compared topical skin care products alongside frequencies of application. One trial compared frequencies of application of topical skin care products.We found evidence in two trials, being of low and moderate quality, that soap and water performed poorly in the prevention and treatment of IAD (primary outcomes of this review). The first trial indicated that the use of a skin cleanser might be more effective than the use of soap and water (risk ratio (RR) 0.39, 95% confidence interval (CI) 0.17 to 0.87; low quality evidence). The second trial indicated that a structured skin care procedure, being a washcloth with cleansing, moisturising, and protecting properties, might be more effective than soap and water (RR 0.31, 95% CI 0.12 to 0.79; moderate quality evidence). Findings from the other trials, all being of low to very low quality, suggest that applying a leave-on product (moisturiser, skin protectant, or a combination) might be more effective than not applying a leave-on product. No trial reported on the third primary outcome 'number of participants not satisfied with treatment' or on adverse effects. AUTHORS' CONCLUSIONS: Little evidence, of very low to moderate quality, exists on the effects of interventions for preventing and treating IAD in adults. Soap and water performed poorly in the prevention and treatment of IAD. Application of leave-on products (moisturisers, skin protectants, or a combination) and avoiding soap seems to be more effective than withholding these products. The performance of leave-on products depends on the combination of ingredients, the overall formulation and the usage (e.g. amount applied). High quality confirmatory trials using standardised, and comparable prevention and treatment regimens in different settings/regions are required. Furthermore, to increase the comparability of trial results, we recommend the development of a core outcome set, including validated measurement tools. The evidence in this review is current up to 28 September 2016.

A yeast-based model of alpha-synucleinopathy identifies compounds with therapeutic potential.

We have developed a yeast-based model recapitulating neurotoxicity of alpha-synuclein fibrilization. This model recognized metal ions, known risk factors of alpha-synucleinopathy, as stimulators of alpha-synuclein aggregation and cytotoxicity. Elimination of Yca1 caspase activity augmented both cytotoxicity and inclusion body formation, suggesting the involvement of apoptotic pathway components in toxic alpha-synuclein amyloidogenesis. Deletion of hydrophobic amino acids at positions 66-74 in alpha-synuclein reduced its cytotoxicity but, remarkably, did not lower the levels of insoluble alpha-synuclein, indicating that noxious alpha-synuclein species are different from insoluble aggregates. A compound screen aimed at finding molecules with therapeutic potential identified flavonoids with strong activity to restrain alpha-synuclein toxicity. Subsequent structure-activity analysis elucidated that these acted by virtue of anti-oxidant and metal-chelating activities. In conclusion, this yeast-cell model as presented allows not only fundamental studies related to mechanisms of alpha-synuclein-instigated cellular degeneration, but is also a valid high-throughput identification tool for novel neuroprotective agents.