The impact of digital technology use on nurses' professional identity and relations of power: a literature review.

AIM: This study seeks to review how the use of digital technologies in clinical nursing affects nurses' professional identity and the relations of power within clinical environments. DESIGN: Literature review. DATA SOURCES: PubMed and CINAHL databases were searched in April 2023. METHODS: We screened 874 studies in English and German, of which 15 were included in our final synthesis reflecting the scientific discourse from 1992 until 2023. RESULTS: Our review revealed relevant effects of digital technologies on nurses' professional identity and power relations. Few studies cover outcomes relating to identity, such as moral agency or nurses' autonomy. Most studies describe negative impacts of technology on professional identity, for example, creating a barrier between nurses and patients leading to decreased empathetic interaction. Regarding power relations, technologically skilled nurses can yield power over colleagues and patients, while depending on technology. The investigation of these effects is underrepresented. CONCLUSION: Our review presents insights into the relation between technology and nurses' professional identity and prevalent power relations. For future studies, dedicated and critical investigations of digital technologies' impact on the formation of professional identity in nursing are required. IMPLICATIONS FOR THE PROFESSION: Nurses' professional identity may be altered by digital technologies used in clinical care. Nurses, who are aware of the potential effects of digitized work environments, can reflect on the relationship of technology and the nursing profession. IMPACT: The use of digital technology might lead to a decrease in nurses' moral agency and competence to shape patient-centred care. Digital technologies seem to become an essential measure for nurses to wield power over patients and colleagues, whilst being a control mechanism. Our work encourages nurses to actively shape digital care. REPORTING METHOD: We adhere to the JBI Manual for Evidence Synthesis where applicable. EQUATOR reporting guidelines were not applicable for this type of review. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Correction: Comparison of Four Active SARS-CoV-2 Surveillance Strategies in Representative Population Sample Points: Two-Factor Factorial Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/44204.].

Inhibition of 26S proteasome activity by α-synuclein is mediated by the proteasomal chaperone Rpn14/PAAF1.

Parkinson's disease (PD) is characterized by aggregation of α-synuclein (α-syn) into protein inclusions in degenerating brains. Increasing amounts of aggregated α-syn species indicate significant perturbation of cellular proteostasis. Altered proteostasis depends on α-syn protein levels and the impact of α-syn on other components of the proteostasis network. Budding yeast Saccharomyces cerevisiae was used as eukaryotic reference organism to study the consequences of α-syn expression on protein dynamics. To address this, we investigated the impact of overexpression of α-syn and S129A variant on the abundance and stability of most yeast proteins using a genome-wide yeast library and a tandem fluorescent protein timer (tFT) reporter as a measure for protein stability. This revealed that the stability of in total 377 cellular proteins was altered by α-syn expression, and that the impact on protein stability was significantly enhanced by phosphorylation at Ser129 (pS129). The proteasome assembly chaperone Rpn14 was identified as one of the top candidates for increased protein stability by expression of pS129 α-syn. Elevated levels of Rpn14 enhanced the growth inhibition by α-syn and the accumulation of ubiquitin conjugates in the cell. We found that Rpn14 interacts physically with α-syn and stabilizes pS129 α-syn. The expression of α-syn along with elevated levels of Rpn14 or its human counterpart PAAF1 reduced the proteasome activity in yeast and in human cells, supporting that pS129 α-syn negatively affects the 26S proteasome through Rpn14. This comprehensive study into the alternations of protein homeostasis highlights the critical role of the Rpn14/PAAF1 in α-syn-mediated proteasome dysfunction.

Proteome-wide tagging with an H2O2 biosensor reveals highly localized and dynamic redox microenvironments.

Hydrogen peroxide (H2O2) sensing and signaling involves the reversible oxidation of particular thiols on particular proteins to modulate protein function in a dynamic manner. H2O2 can be generated from various intracellular sources, but their identities and relative contributions are often unknown. To identify endogenous "hotspots" of H2O2 generation on the scale of individual proteins and protein complexes, we generated a yeast library in which the H2O2 sensor HyPer7 was fused to the C-terminus of all protein-coding open reading frames (ORFs). We also generated a control library in which a redox-insensitive mutant of HyPer7 (SypHer7) was fused to all ORFs. Both libraries were screened side-by-side to identify proteins located within H2O2-generating environments. Screening under a variety of different metabolic conditions revealed dynamic changes in H2O2 availability highly specific to individual proteins and protein complexes. These findings suggest that intracellular H2O2 generation is much more localized and functionally differentiated than previously recognized.

Building yeast libraries to dissect terminal degrons with fluorescent timers.

Selective degradation of unnecessary or abnormal proteins by the ubiquitin-proteasome system is an essential part of proteostasis. Ubiquitin ligases recognize substrates of selective protein degradation and modify them with polyubiquitin chains, which mark them for proteasomal degradation. Substrate recognition by ubiquitin ligases often involves degradation signals or degrons, which are typically short linear motifs found in intrinsically disordered regions, e.g., at protein termini. However, specificity in selective protein degradation is generally not well understood, as for most ubiquitin ligases no degrons have been identified thus far. To address this limitation, high-throughput mutagenesis approaches, such as multiplexed protein stability (MPS) profiling, have been developed, enabling systematic surveys of degrons in vivo or allowing to define degron motifs recognized by different ubiquitin ligases. In MPS profiling, thousands of short peptides can be assessed in parallel for their ability to trigger degradation of a fluorescent timer reporter. Here, we describe common types of libraries used to identify and dissect degrons located at protein termini using MPS profiling in budding yeast, and provide protocols for their construction.

Multiplexed protein stability (MPS) profiling of terminal degrons using fluorescent timer libraries in Saccharomyces cerevisiae.

N-terminal protein sequences and their proteolytic processing and modifications influence the stability and turnover of proteins by creating potential degrons for cellular proteolytic pathways. Understanding the impact of genetic perturbations of components affecting the processing of protein N-termini and thereby their stability, requires methods compatible with proteome-wide studies of many N-termini simultaneously. Tandem fluorescent timers (tFT) allow the in vivo measurement of protein turnover completely independent of protein abundance and can be deployed for proteome-wide studies. Here we present a protocol for Multiplexed Protein Stability (MPS) profiling of tFT-libraries encoding large numbers of different protein N-termini fused to tFT in the yeast Saccharomyces cerevisiae. This protocol includes fluorescence cell sorting based profiling of these libraries using a pooling approach. Analysis of the sorted pools is done by using multiplexed deep sequencing, in order to generate a stability index for each N-terminally peptide fused to the tFT reporter, and to evaluate half-life changes across all species represented in the library.

Comparison of Four Active SARS-CoV-2 Surveillance Strategies in Representative Population Sample Points: Two-Factor Factorial Randomized Controlled Trial.

BACKGROUND: The COVID-19 pandemic is characterized by rapid increases in infection burden owing to the emergence of new variants with higher transmissibility and immune escape. To date, monitoring the COVID-19 pandemic has mainly relied on passive surveillance, yielding biased epidemiological measures owing to the disproportionate number of undetected asymptomatic cases. Active surveillance could provide accurate estimates of the true prevalence to forecast the evolution of the pandemic, enabling evidence-based decision-making. OBJECTIVE: This study compared 4 different approaches of active SARS-CoV-2 surveillance focusing on feasibility and epidemiological outcomes. METHODS: A 2-factor factorial randomized controlled trial was conducted in 2020 in a German district with 700,000 inhabitants. The epidemiological outcome comprised SARS-CoV-2 prevalence and its precision. The 4 study arms combined 2 factors: individuals versus households and direct testing versus testing conditioned on symptom prescreening. Individuals aged ≥7 years were eligible. Altogether, 27,908 addresses from 51 municipalities were randomly allocated to the arms and 15 consecutive recruitment weekdays. Data collection and logistics were highly digitized, and a website in 5 languages enabled low-barrier registration and tracking of results. Gargle sample collection kits were sent by post. Participants collected a gargle sample at home and mailed it to the laboratory. Samples were analyzed with reverse transcription loop-mediated isothermal amplification (RT-LAMP); positive and weak results were confirmed with real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Recruitment was conducted between November 18 and December 11, 2020. The response rates in the 4 arms varied between 34.31% (2340/6821) and 41.17% (2043/4962). The prescreening classified 16.61% (1207/7266) of the patients as COVID-19 symptomatic. Altogether, 4232 persons without prescreening and 7623 participating in the prescreening provided 5351 gargle samples, of which 5319 (99.4%) could be analyzed. This yielded 17 confirmed SARS-CoV-2 infections and a combined prevalence of 0.36% (95% CI 0.14%-0.59%) in the arms without prescreening and 0.05% (95% CI 0.00%-0.108%) in the arms with prescreening (initial contacts only). Specifically, we found a prevalence of 0.31% (95% CI 0.06%-0.58%) for individuals and 0.35% (95% CI 0.09%-0.61%) for households, and lower estimates with prescreening (0.07%, 95% CI 0.0%-0.15% for individuals and 0.02%, 95% CI 0.0%-0.06% for households). Asymptomatic infections occurred in 27% (3/11) of the positive cases with symptom data. The 2 arms without prescreening performed the best regarding effectiveness and accuracy. CONCLUSIONS: This study showed that postal mailing of gargle sample kits and returning home-based self-collected liquid gargle samples followed by high-sensitivity RT-LAMP analysis is a feasible way to conduct active SARS-CoV-2 population surveillance without burdening routine diagnostic testing. Efforts to improve participation rates and integration into the public health system may increase the potential to monitor the course of the pandemic. TRIAL REGISTRATION: Deutsches Register Klinischer Studien (DRKS) DRKS00023271; https://tinyurl.com/3xenz68a. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-021-05619-5.

Components of TOR and MAP kinase signaling control chemotropism and pathogenicity in the fungal pathogen Verticillium dahliae.

Filamentous fungi can sense useful resources and hazards in their environment and direct growth of their hyphae accordingly. Chemotropism ensures access to nutrients, contact with other individuals (e.g., for mating), and interaction with hosts in the case of pathogens. Previous studies have revealed a complex chemotropic sensing landscape during host-pathogen interactions, but the underlying molecular machinery remains poorly characterized. Here we studied mechanisms controlling directed hyphal growth of the important plant-pathogenic fungus Verticillium dahliae towards different chemoattractants. We found that the homologs of the Rag GTPase Gtr1 and the GTPase-activating protein Tsc2, an activator and a repressor of the TOR kinase respectively, play important roles in hyphal chemotropism towards nutrients, plant-derived signals, and heterologous α-pheromone of Fusarium oxysporum. Furthermore, important roles of these regulators were identified in fungal development and pathogenicity. We also found that the mitogen-activated protein kinase (MAPK) Fus3 is required for chemotropism towards nutrients, while the G protein-coupled receptor (GPCR) Ste2 and the MAPK Slt2 control chemosensing of plant-derived signals and α-pheromone. Our study establishes V. dahliae as a suitable model system for the analysis of fungal chemotropism and discovers new components of chemotropic signaling during growth and host-pathogen interactions of V. dahliae.

Scalable RT-LAMP-based SARS-CoV-2 testing for infection surveillance with applications in pandemic preparedness.

Throughout the SARS-CoV-2 pandemic, limited diagnostic capacities prevented sentinel testing, demonstrating the need for novel testing infrastructures. Here, we describe the setup of a cost-effective platform that can be employed in a high-throughput manner, which allows surveillance testing as an acute pandemic control and preparedness tool, exemplified by SARS-CoV-2 diagnostics in an academic environment. The strategy involves self-sampling based on gargling saline, pseudonymized sample handling, automated RNA extraction, and viral RNA detection using a semiquantitative multiplexed colorimetric reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay with an analytical sensitivity comparable with RT-qPCR. We provide standard operating procedures and an integrated software solution for all workflows, including sample logistics, analysis by colorimetry or sequencing, and communication of results. We evaluated factors affecting the viral load and the stability of gargling samples as well as the diagnostic sensitivity of the RT-LAMP assay. In parallel, we estimated the economic costs of setting up and running the test station. We performed > 35,000 tests, with an average turnover time of < 6 h from sample arrival to result announcement. Altogether, our work provides a blueprint for fast, sensitive, scalable, cost- and labor-efficient RT-LAMP diagnostics, which is independent of potentially limiting clinical diagnostics supply chains.

Cost and cost-effectiveness of four different SARS-CoV-2 active surveillance strategies: evidence from a randomised control trial in Germany.

INTRODUCTION: The COVID-19 pandemic has entered its third year and continues to affect most countries worldwide. Active surveillance, i.e. testing individuals irrespective of symptoms, presents a promising strategy to accurately measure the prevalence of SARS-CoV-2. We aimed to identify the most cost-effective active surveillance strategy for COVID-19 among the four strategies tested in a randomised control trial between 18th November 2020 and 23rd December 2020 in Germany. The four strategies included: (A1) direct testing of individuals; (A2) direct testing of households; (B1) testing conditioned on upstream COVID-19 symptom pre-screening of individuals; and (B2) testing conditioned on upstream COVID-19 symptom pre-screening of households. METHODS: We adopted a health system perspective and followed an activity-based approach to costing. Resource consumption data were collected prospectively from a digital individual database, daily time records, key informant interviews and direct observations. Our cost-effectiveness analysis compared each strategy with the status quo and calculated the average cost-effective ratios (ACERs) for one primary outcome (sample tested) and three secondary outcomes (responder recruited, case detected and asymptomatic case detected). RESULTS: Our results showed that A2, with cost per sample tested at 52,89 EURO, had the lowest ACER for the primary outcome, closely followed by A1 (63,33 EURO). This estimate was much higher for both B1 (243,84 EURO) and B2 (181,06 EURO). CONCLUSION: A2 (direct testing at household level) proved to be the most cost-effective of the four evaluated strategies and should be considered as an option to strengthen the routine surveillance system in Germany and similar settings.

SWR1 chromatin remodeling complex prevents mitotic slippage during spindle position checkpoint arrest.

Faithful chromosome segregation in budding yeast requires correct positioning of the mitotic spindle along the mother to daughter cell polarity axis. When the anaphase spindle is not correctly positioned, a surveillance mechanism, named as the spindle position checkpoint (SPOC), prevents the progression out of mitosis until correct spindle positioning is achieved. How SPOC works on a molecular level is not well understood. Here we performed a genome-wide genetic screen to search for components required for SPOC. We identified the SWR1 chromatin-remodeling complex (SWR1-C) among several novel factors that are essential for SPOC integrity. Cells lacking SWR1-C were able to activate SPOC upon spindle misorientation but underwent mitotic slippage upon prolonged SPOC arrest. This mitotic slippage required the Cdc14-early anaphase release pathway and other factors including the SAGA (Spt-Ada-Gcn5 acetyltransferase) histone acetyltransferase complex, proteasome components and the mitotic cyclin-dependent kinase inhibitor Sic1. Together, our data establish a novel link between SWR1-C chromatin remodeling and robust checkpoint arrest in late anaphase.

Rapid comparative evaluation of SARS-CoV-2 rapid point-of-care antigen tests.

PURPOSE: The objective of this study was to develop a scalable approach for direct comparison of the analytical sensitivities of commercially available SARS-CoV-2 antigen point-of-care tests (AgPOCTs) to rapidly identify poor-performing products. METHODS: We present a methodology for quick assessment of the sensitivity of SARS-CoV-2 AgPOCTs suitable for quality evaluation of many different products. We established reference samples with high, medium, and low SARS-CoV-2 viral loads along with a SARS-CoV-2 negative control sample. Test samples were used to semi-quantitatively assess the analytical sensitivities of 32 different commercial AgPOCTs in a head-to-head comparison. RESULTS: Among 32 SARS-CoV-2 AgPOCTs tested, we observe sensitivity differences across a broad range of viral loads (9.8 × 108 to 1.8 × 105 SARS-CoV-2 genome copies per ml). 23 AgPOCTs detected the Ct25 test sample (1.6 × 106 copies/ml), while only five tests detected the Ct28 test sample (1.8 × 105 copies/ml). In the low-range of analytical sensitivity, we found three saliva spit tests only delivering positive results for the Ct21 sample (2.7 × 107 copies/ml). Comparison with published data supports our AgPOCT ranking. Importantly, we identified an AgPOCT widely offered, which did not reliably recognize the sample with the highest viral load (Ct16 test sample with 9.8 × 108 copies/ml) leading to serious doubts about its usefulness in SARS-CoV-2 diagnostics. CONCLUSION: The results show that the rapid sensitivity assessment procedure presented here provides useful estimations on the analytical sensitivities of 32 AgPOCTs and identified a widely-spread AgPOCT with concerningly low sensitivity.

Human Factors and Technological Characteristics Influencing the Interaction of Medical Professionals With Artificial Intelligence-Enabled Clinical Decision Support Systems: Literature Review.

BACKGROUND: The digitization and automation of diagnostics and treatments promise to alter the quality of health care and improve patient outcomes, whereas the undersupply of medical personnel, high workload on medical professionals, and medical case complexity increase. Clinical decision support systems (CDSSs) have been proven to help medical professionals in their everyday work through their ability to process vast amounts of patient information. However, comprehensive adoption is partially disrupted by specific technological and personal characteristics. With the rise of artificial intelligence (AI), CDSSs have become an adaptive technology with human-like capabilities and are able to learn and change their characteristics over time. However, research has not reflected on the characteristics and factors essential for effective collaboration between human actors and AI-enabled CDSSs. OBJECTIVE: Our study aims to summarize the factors influencing effective collaboration between medical professionals and AI-enabled CDSSs. These factors are essential for medical professionals, management, and technology designers to reflect on the adoption, implementation, and development of an AI-enabled CDSS. METHODS: We conducted a literature review including 3 different meta-databases, screening over 1000 articles and including 101 articles for full-text assessment. Of the 101 articles, 7 (6.9%) met our inclusion criteria and were analyzed for our synthesis. RESULTS: We identified the technological characteristics and human factors that appear to have an essential effect on the collaboration of medical professionals and AI-enabled CDSSs in accordance with our research objective, namely, training data quality, performance, explainability, adaptability, medical expertise, technological expertise, personality, cognitive biases, and trust. Comparing our results with those from research on non-AI CDSSs, some characteristics and factors retain their importance, whereas others gain or lose relevance owing to the uniqueness of human-AI interactions. However, only a few (1/7, 14%) studies have mentioned the theoretical foundations and patient outcomes related to AI-enabled CDSSs. CONCLUSIONS: Our study provides a comprehensive overview of the relevant characteristics and factors that influence the interaction and collaboration between medical professionals and AI-enabled CDSSs. Rather limited theoretical foundations currently hinder the possibility of creating adequate concepts and models to explain and predict the interrelations between these characteristics and factors. For an appropriate evaluation of the human-AI collaboration, patient outcomes and the role of patients in the decision-making process should be considered.

Up-regulation of ubiquitin-proteasome activity upon loss of NatA-dependent N-terminal acetylation.

N-terminal acetylation is a prominent protein modification, and inactivation of N-terminal acetyltransferases (NATs) cause protein homeostasis stress. Using multiplexed protein stability profiling with linear ubiquitin fusions as reporters for the activity of the ubiquitin proteasome system, we observed increased ubiquitin proteasome system activity in NatA, but not NatB or NatC mutants. We find several mechanisms contributing to this behavior. First, NatA-mediated acetylation of the N-terminal ubiquitin-independent degron regulates the abundance of Rpn4, the master regulator of the expression of proteasomal genes. Second, the abundance of several E3 ligases involved in degradation of UFD substrates is increased in cells lacking NatA. Finally, we identify the E3 ligase Tom1 as a novel chain-elongating enzyme (E4) involved in the degradation of linear ubiquitin fusions via the formation of branched K11, K29, and K48 ubiquitin chains, independently of the known E4 ligases involved in UFD, leading to enhanced ubiquitination of the UFD substrates.

From disgusting and complicated to simple and brilliant: Implementation perspectives and lessons learned from users and rejectors of mail-in SARS-CoV-2 gargle tests.

Background: Despite the important role of testing as a measure against the COVID-19 pandemic, user perspectives on SARS-CoV-2 tests remain scarce, inhibiting an improvement of testing approaches. As the world enters the third year of the pandemic, more nuanced perspectives of testing, and opportunities to expand testing in a feasible and affordable manner merit consideration. Methods: Conducted amid the second pandemic wave (late 2020-early 2021) during and after a multi-arm trial evaluating SARS-CoV-2 surveillance strategies in the federal state Baden-Württemberg, Germany, this qualitative sub-study aimed to gain a deeper understanding of how test users and test rejectors perceived mail-in SARS-CoV-2 gargle tests. We conducted 67 semi-structured in-depth interviews (mean duration: 60 min) via telephone or video call. Interviews were audio-recorded, transcribed verbatim and analyzed inductively using thematic analysis. The Consolidated Framework for Implementation Research guided the findings' presentation. Results: Respondents generally described gargle sampling as simple and comfortable. However, individual perceptions of the testing method and its feasibility varied widely from disgusting and complicated to simple and brilliant. Self-sampling was appreciated for lowering infection risks during testing, but also considered more complex. Gargle-sampling increased participants' self-efficacy to sample correctly. Communication (first contact, quantity and content of information, reminders, support system) and trust (in the study, its institutional affiliation and test method) decisively influenced the intervention's acceptability. Conclusion: User-driven insights on how to streamline testing include: consider communication, first impressions of tests and information as key for successful mail-in testing; pay attention to the role of mutual trust between those taking and administering tests; implement gargle self-sampling as a pleasant alternative to swab testing; offer multiple test methods to increase test up-take.

Sex without crossing over in the yeast Saccharomycodes ludwigii.

BACKGROUND: Intermixing of genomes through meiotic reassortment and recombination of homologous chromosomes is a unifying theme of sexual reproduction in eukaryotic organisms and is considered crucial for their adaptive evolution. Previous studies of the budding yeast species Saccharomycodes ludwigii suggested that meiotic crossing over might be absent from its sexual life cycle, which is predominated by fertilization within the meiotic tetrad. RESULTS: We demonstrate that recombination is extremely suppressed during meiosis in Sd. ludwigii. DNA double-strand break formation by the conserved transesterase Spo11, processing and repair involving interhomolog interactions are required for normal meiosis but do not lead to crossing over. Although the species has retained an intact meiotic gene repertoire, genetic and population analyses suggest the exceptionally rare occurrence of meiotic crossovers in its genome. A strong AT bias of spontaneous mutations and the absence of recombination are likely responsible for its unusually low genomic GC level. CONCLUSIONS: Sd. ludwigii has followed a unique evolutionary trajectory that possibly derives fitness benefits from the combination of frequent mating between products of the same meiotic event with the extreme suppression of meiotic recombination. This life style ensures preservation of heterozygosity throughout its genome and may enable the species to adapt to its environment and survive with only minimal levels of rare meiotic recombination. We propose Sd. ludwigii as an excellent natural forum for the study of genome evolution and recombination rates.

The NADPH Oxidase A of Verticillium dahliae Is Essential for Pathogenicity, Normal Development, and Stress Tolerance, and It Interacts with Yap1 to Regulate Redox Homeostasis.

Maintenance of redox homeostasis is vital for aerobic organisms and particularly relevant to plant pathogens. A balance is required between their endogenous ROS production, which is important for their development and pathogenicity, and host-derived oxidative stress. Endogenous ROS in fungi are generated by membrane-bound NADPH oxidase (NOX) complexes and the mitochondrial respiratory chain, while transcription factor Yap1 is a major regulator of the antioxidant response. Here, we investigated the roles of NoxA and Yap1 in fundamental biological processes of the important plant pathogen Verticillium dahliae. Deletion of noxA impaired growth and morphogenesis, compromised formation of hyphopodia, diminished penetration ability and pathogenicity, increased sensitivity against antifungal agents, and dysregulated expression of antioxidant genes. On the other hand, deletion of yap1 resulted in defects in conidial and microsclerotia formation, increased sensitivity against oxidative stress, and down-regulated antioxidant genes. Localized accumulation of ROS was observed before conidial fusion and during the heterokaryon incompatibility reaction upon nonself fusion. The frequency of inviable fusions was not affected by the deletion of Yap1. Analysis of a double knockout mutant revealed an epistatic relationship between noxA and yap1. Our results collectively reveal instrumental roles of NoxA and ROS homeostasis in the biology of V. dahliae.

α-Synuclein Decreases the Abundance of Proteasome Subunits and Alters Ubiquitin Conjugates in Yeast.

Parkinson's disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity.

Effectiveness and cost-effectiveness of four different strategies for SARS-CoV-2 surveillance in the general population (CoV-Surv Study): study protocol for a two-factorial randomized controlled multi-arm trial with cluster sampling.

BACKGROUND: To achieve higher effectiveness in population-based SARS-CoV-2 surveillance and to reliably predict the course of an outbreak, screening, and monitoring of infected individuals without major symptoms (about 40% of the population) will be necessary. While current testing capacities are also used to identify such asymptomatic cases, this rather passive approach is not suitable in generating reliable population-based estimates of the prevalence of asymptomatic carriers to allow any dependable predictions on the course of the pandemic. METHODS: This trial implements a two-factorial, randomized, controlled, multi-arm, prospective, interventional, single-blinded design with cluster sampling and four study arms, each representing a different SARS-CoV-2 testing and surveillance strategy based on individuals' self-collection of saliva samples which are then sent to and analyzed by a laboratory. The targeted sample size for the trial is 10,000 saliva samples equally allocated to the four study arms (2500 participants per arm). Strategies differ with respect to tested population groups (individuals vs. all household members) and testing approach (without vs. with pre-screening survey). The trial is complemented by an economic evaluation and qualitative assessment of user experiences. Primary outcomes include costs per completely screened person, costs per positive case, positive detection rate, and precision of positive detection rate. DISCUSSION: Systems for active surveillance of the general population will gain more importance in the context of pandemics and related disease prevention efforts. The pandemic parameters derived from such active surveillance with routine population monitoring therefore not only enable a prospective assessment of the short-term course of a pandemic, but also a more targeted and thus more effective use of local and short-term countermeasures. TRIAL REGISTRATION: ClinicalTrials.gov DRKS00023271 . Registered November 30, 2020, with the German Clinical Trials Register (Deutsches Register Klinischer Studien).

Investigating the Use of Telemedicine for Digitally Mediated Delegation in Team-Based Primary Care: Mixed Methods Study.

BACKGROUND: Owing to the shortage of medical professionals, as well as demographic and structural challenges, new care models have emerged to find innovative solutions to counter medical undersupply. Team-based primary care using medical delegation appears to be a promising approach to address these challenges; however, it demands efficient communication structures and mechanisms to reinsure patients and caregivers receive a delegated, treatment-related task. Digital health care technologies hold the potential to render these novel processes effective and demand driven. OBJECTIVE: The goal of this study is to recreate the daily work routines of general practitioners (GPs) and medical assistants (MAs) to explore promising approaches for the digital moderation of delegation processes and to deepen the understanding of subjective and perceptual factors that influence their technology assessment and use. METHODS: We conducted a combination of 19 individual and group interviews with 12 GPs and 14 MAs, seeking to identify relevant technologies for delegation purposes as well as stakeholders' perceptions of their effectiveness. Furthermore, a web-based survey was conducted asking the interviewees to order identified technologies based on their assessed applicability in multi-actor patient care. Interview data were analyzed using a three-fold inductive coding procedure. Multidimensional scaling was applied to analyze and visualize the survey data, leading to a triangulation of the results. RESULTS: Our results suggest that digital mediation of delegation underlies complex, reciprocal processes and biases that need to be identified and analyzed to improve the development and distribution of innovative technologies and to improve our understanding of technology use in team-based primary care. Nevertheless, medical delegation enhanced by digital technologies, such as video consultations, portable electrocardiograms, or telemedical stethoscopes, can counteract current challenges in primary care because of its unique ability to ensure both personal, patient-centered care for patients and create efficient and needs-based treatment processes. CONCLUSIONS: Technology-mediated delegation appears to be a promising approach to implement innovative, case-sensitive, and cost-effective ways to treat patients within the paradigm of primary care. The relevance of such innovative approaches increases with the tremendous need for differentiated and effective care, such as during the ongoing COVID-19 pandemic. For the successful and sustainable adoption of innovative technologies, MAs represent essential team members. In their role as mediators between GPs and patients, MAs are potentially able to counteract patients' resistance toward using innovative technology and compensate for patients' limited access to technology and care facilities.