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Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD. Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t0) and after 12 (±4) (t1) and 24 (±4) (t2) months. Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t2. Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t2 (p = 0.0031). Neither the mean t0 to t1 change (Δ) of DLCO nor the mean t0 to t1 FVCΔ predicted the appearance of ILD at t2. Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t0 DLCO < 80%, stronger than that of FVC < 80%. Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

Abstract Background Abnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects. Methods Lymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation. Results SSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc. Conclusion In this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.

Introduction Inflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, are characterised by inflammatory infiltration of the joints. Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), respectively, reduce the effects of proinflammatory cytokines and immune cells to ameliorate disease. However, immunosuppression can be associated with high rates of serious adverse events (SAEs), including serious infections, and maybe an increased risk of malignancies and cardiovascular events. Currently, there is no empirical evidence on the extent to which contextual factors and risk of bias (RoB) domains may modify these harm signals in randomised trials.Methods and analysis We will search MEDLINE (via PubMed) for systematic reviews published since April 2015 and all Cochrane reviews. From these reviews, randomised trials will be eligible if they include patients with an IA condition with at least one group randomly allocated to bDMARD and/or tsDMARD treatments. A predefined form will be used for extracting data on population characteristics (eg, baseline characteristics or eligibility criteria, such as medication background) and specific harm outcome measures, such as number of withdrawals, numbers of patients discontinuing due to adverse events and number of patients having SAEs. RoB in individual trials will be assessed using a modified Cochrane RoB tool. We will estimate the potentially causal harm effects related to the experimental intervention compared with control comparator as risk ratios, and heterogeneity across randomised comparisons will be assessed statistically and evaluated as inconsistency using the I2 Index. Our metaregression analyses will designate population and trial characteristics and each RoB domain as independent variables, whereas the three harm domains will serve as dependent variables.Ethics and dissemination Ethics approval is not required for this study. Results will be disseminated through publication in international peer-reviewed journals.PROSPERO registration number CRD42020171124.

An amendment to this paper has been published and can be accessed via the original article.

We propose a categorization of smartwatch use in the health care sector into 3 key functional domains: monitoring, nudging, and predicting. Monitoring involves using smartwatches within medical treatments to track health data, nudging pertains to individual use for health purposes outside a particular medical setting, and predicting involves using aggregated user data to train machine learning algorithms to predict health outcomes. Each domain offers unique contributions to health care, yet there is a lack of nuanced discussion in existing research. This paper not only provides an overview of recent technological advancements in consumer smartwatches but also explores the 3 domains in detail, culminating in a comprehensive summary that anticipates the future value and impact of smartwatches in health care. By dissecting the interconnected challenges and potentials, this paper aims to enhance the understanding and effective deployment of smartwatches in value-based health care.

BackgroundManagement of sedation, analgesia, and delirium influences morbidity, mortality, and quality of life in patients treated in intensive care. Assessing quality indicators as part of a quality management and assurance program is an established method to ensure process quality. Currently, there is limited research on the effect of evaluating quality indicators on economic outcomes. The aim of the study was to investigate the adherence to an indicator on management of sedation, analgesia and delirium, and explore potential effects on hospital economics and clinical outcomes.MethodsIn this retrospective cohort study, we analyzed routine data from 20,220 patient records from the hospital information system of a tertiary university hospital, collected from January 2012 to December 2019. We compared two predefined subgroups with either high indicator adherence or low indicator adherence regarding factors like disease severity scores, comorbidities, and outcome measures. We used logistic regression models to examine the influence of quality indicator adherence on economic measures such as Diagnosis-related group (DRG) incomes, revenue margins, and costs, and clinical outcomes. Additionally, we used propensity score matching to probe our findings.ResultsOverall revenue margins in this cohort were negative (-320€). High adherence to the quality indicator was associated with a positive revenue margin (+197€) compared to low adherence (-482€). Higher adherence was also associated with lower costs. Additionally, high adherence was associated with reduced mortality (OR 0.84, 95% CI 0.75-0.95) and reduced duration of mechanical ventilation and hospital stay (17 hours and 1 day respectively).ConclusionHigher adherence to a quality indicator for sedation, analgesia, and delirium management was associated with economic returns and costs. We also found an association with lower mortality and reduced length of stay. Further research on these associations may help identify opportunities for quality improvement without increased resource use.

The complement system plays a crucial role in host defense, homeostasis, and tissue regeneration and bridges the innate and the adaptive immune systems. Although the genetic variants in complement C2 (c.839_849+17del; p.(Met280Asnfs*5)) and C8B (c.1625C>T; p.(Thr542Ile)) are known individually, here, we report on a patient carrying their combination in a heterozygous form. The patient presented with a reduced general condition and suffers from a wide variety of autoimmune diseases. While no autoimmune disease-specific autoantibodies could be detected, genetic analysis revealed abnormalities in the two complement genes C2 and C8B. Therefore, we performed a comprehensive investigation of the innate immune system on a cellular and humoral level to define the functional consequences. We found slightly impaired functionality of neutrophils and monocytes regarding phagocytosis and reactive oxygen species generation and a diminished expression of the C5aR1. An extensive complement analysis revealed a declined activation potential for the alternative and classical pathway. Reconstitution with purified C2 and C8 into patient serum failed to normalize the dysfunction, whereas the addition of C3 improved the hemolytic activity. In clinical transfer, in vitro supplementation of the patient’s plasma with FFP as a complement source could fully restore full complement functionality. This study describes for the first time a combined heterozygous genetic variation in complement C2 and C8B which, however, cannot fully explain the overall dysfunctions and calls for further complement deficiency research and corresponding therapies.

BackgroundThe circular economy reshapes the linear “take, make, and dispose” approach and evolves around minimizing waste and recapturing resources in a closed-loop system. The health sector accounts for 4.6% of global greenhouse gas emissions and has, over the decades, been built to rely on single-use devices and deal with high volumes of medical waste. With the increase in the adoption of digital health solutions in the health care industry, leading the industry into a new paradigm of how we provide health care, a focus must be put on the amount of waste that will follow. Digital health solutions will shape health care through the use of technology and lead to improved patient care, but they will also make medical waste more complex to deal with due to the e-waste component. Therefore, a transformation of the health care industry to a circular economy is a crucial cornerstone in decreasing the impact on the environment. ObjectiveThis study aims to address the lack of direction in the current literature on circular business models. It will consider micro, meso, and macro factors that would impact the operational validity of circular models using the digital health solutions ePaper label (medical packaging), smart wearable sensor (health monitoring devices), smart pill box (medication management), and endo-cutter (surgical equipment) as examples. MethodsThe study will systematically perform a scoping review through a database and snowball search. We will analyze and classify the studies from a predetermined set of categories and then summarize them into an evidence map. Based on the review, the study will develop a 2D framework for businesses to follow or for future research to take a standpoint from. ResultsPreliminarily, the review has analyzed 26 studies in total. The results are close to equally distributed among the micro (8/26, 31%), meso (10/26, 38%), and macro (8/26, 31%) levels. Circular economy studies emphasize several circular practices such as recycling (17/26, 65%), reusing (18/26, 69%), reducing (15/26, 58%), and remanufacturing (8/26, 31%). The value proposition in the examined business model is mostly dominated by stand-alone products (18/26, 69%) compared to product as a service (7/26, 27%), involving stakeholders such as health care professionals or hospitals (20/26, 77%), manufacturers (11/26, 42%), and consumers (9/26, 35%). All studies encompass societal (12/26, 46%), economic (23/26, 88%), and environmental (24/26, 92%) viewpoints. ConclusionsThe study argues that each digital health solution would have to be accessed individually to find the optimal business model to follow. This is due to their differing life cycles and complexity. The manufacturer will need a layered value proposition, implementing several business models dependent on their respective product portfolios. The need to incorporate several business models implies an ecosystem perspective that is relevant to consider. International Registered Report Identifier (IRRID)DERR1-10.2196/47874

Abstract Background Shared decision-making (SDM) in perioperative care, is an organizational approach to instituting sharing of information and decision-making around surgery. It aims at enabling patient autonomy and patient-centered care. Frail and elderly patients suffering from multiple health conditions and increased surgical vulnerability might particularly benefit from SDM. However, little is known about the facilitators and barriers to implementing SDM in perioperative care for the specific needs of frail and elderly patients. Our objective is twofold: First, we aim at collecting, analyzing, categorizing, and communicating facilitators and barriers. Second, we aim at collecting and mapping conceptual approaches and methods employed in determining and analyzing these facilitators and barriers. Methods The search strategy focused on peer-reviewed studies. We employed a taxonomy which is based on the SPIDER framework and added the items general article information, stakeholder, barriers/facilitators, category, subcategory, and setting/contextual information. This taxonomy is based on preceding reviews. The scoping review is reported under the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews. Based on the databases MEDLINE, Embase, CINAHL, and Web of Science, we screened 984 articles, identified, and reviewed 13 original studies. Results Within this review, two primary facilitators concerning patients’ willingness to participate in SDM emerged: Patients want to be informed on their medical condition and procedures. Patients prefer sharing decisions with healthcare professionals, compared to decision-making solely by patients or decision-making solely by healthcare professionals. Communication issues and asymmetric power relationships between patients and clinical healthcare professionals are barriers to SDM. Regarding the methodological approaches, the evaluation of the conceptual approaches demonstrates that the selected articles lack employing a distinct theoretical framework. Second, the selected studies mainly used surveys and interviews, observational studies, like ethnographic or video-based studies are absent. Conclusion Diverging findings perceived by patients or clinical healthcare professionals were identified. These imply that SDM research related to elderly and frail patients should become more encompassing by employing research that incorporates theory-based qualitative analysis, and observational studies of SDM consultations for understanding practices by patients and clinical healthcare professionals. Observational studies are particularly relevant as these were not conducted. Trial registration https://osf.io/8fjnb/

BackgroundPrevious studies have revealed that users of symptom checkers (SCs, apps that support self-diagnosis and self-triage) are predominantly female, are younger than average, and have higher levels of formal education. Little data are available for Germany, and no study has so far compared usage patterns with people’s awareness of SCs and the perception of usefulness. ObjectiveWe explored the sociodemographic and individual characteristics that are associated with the awareness, usage, and perceived usefulness of SCs in the German population. MethodsWe conducted a cross-sectional online survey among 1084 German residents in July 2022 regarding personal characteristics and people’s awareness and usage of SCs. Using random sampling from a commercial panel, we collected participant responses stratified by gender, state of residence, income, and age to reflect the German population. We analyzed the collected data exploratively. ResultsOf all respondents, 16.3% (177/1084) were aware of SCs and 6.5% (71/1084) had used them before. Those aware of SCs were younger (mean 38.8, SD 14.6 years, vs mean 48.3, SD 15.7 years), were more often female (107/177, 60.5%, vs 453/907, 49.9%), and had higher formal education levels (eg, 72/177, 40.7%, vs 238/907, 26.2%, with a university/college degree) than those unaware. The same observation applied to users compared to nonusers. It disappeared, however, when comparing users to nonusers who were aware of SCs. Among users, 40.8% (29/71) considered these tools useful. Those considering them useful reported higher self-efficacy (mean 4.21, SD 0.66, vs mean 3.63, SD 0.81, on a scale of 1-5) and a higher net household income (mean EUR 2591.63, SD EUR 1103.96 [mean US $2798.96, SD US $1192.28], vs mean EUR 1626.60, SD EUR 649.05 [mean US $1756.73, SD US $700.97]) than those who considered them not useful. More women considered SCs unhelpful (13/44, 29.5%) compared to men (4/26, 15.4%). ConclusionsConcurring with studies from other countries, our findings show associations between sociodemographic characteristics and SC usage in a German sample: users were on average younger, of higher socioeconomic status, and more commonly female compared to nonusers. However, usage cannot be explained by sociodemographic differences alone. It rather seems that sociodemographics explain who is or is not aware of the technology, but those who are aware of SCs are equally likely to use them, independently of sociodemographic differences. Although in some groups (eg, people with anxiety disorder), more participants reported to know and use SCs, they tended to perceive them as less useful. In other groups (eg, male participants), fewer respondents were aware of SCs, but those who used them perceived them to be more useful. Thus, SCs should be designed to fit specific user needs, and strategies should be developed to help reach individuals who could benefit but are not aware of SCs yet.

Objective, design and setting In a cross-sectional patient survey, we examined (a) rates and purposes of mobile phone, computer, internet and social media use, and (b) the role of social and clinical predictors on rates of utilisation among psychiatric inpatients in Berlin, Germany.Participants and results Descriptive analyses showed that among 496 participants, 84.9% owned a mobile phone and 59.3% a smartphone. Among 493 participants, 68.4% used a computer regularly. Multivariate logistic regression models revealed being homeless, diagnosis of a psychotic illness, being of older age and a lower level of education to be significant predictors for not owning a mobile phone, not using a computer regularly or having a social media account, respectively.Conclusions Users of psychiatric services may have access to mobile phones and computers, although rates are lower than in the general population. However, key barriers that need to be addressed regarding the development of and engagement with digital health interventions are factors of social exclusion like marginalised housing as well as clinical aspects like psychotic illness.

IntroductionAntibody mediated rejection (ABMR) is the most common cause of long-term allograft loss in kidney transplantation (KT). Therefore, a low human leukocyte antigen (HLA) mismatch (MM) load is favorable for KT outcomes. Hitherto, serological or low-resolution molecular HLA typing have been adapted in parallel. Here, we aimed to identify previously missed HLA mismatches and corresponding antibodies by high resolution HLA genotyping in a living-donor KT cohort.Methods103 donor/recipient pairs transplanted at the University of Leipzig Medical Center between 1998 and 2018 were re-typed using next generation sequencing (NGS) of the HLA loci -A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1, and -DPB1. Based on these data, we compiled HLA MM counts for each pair and comparatively evaluated genomic HLA-typing with pre-transplant obtained serological/low-resolution HLA (=one-field) typing results. NGS HLA typing (=two-field) data was further used for reclassification of de novo HLA antibodies as “donor-specific”.ResultsBy two-field HLA re-typing, we were able to identify additional MM in 64.1% (n=66) of cases for HLA loci -A, -B, -C, -DRB1 and -DQB1 that were not observed by one-field HLA typing. In patients with biopsy proven ABMR, two-field calculated MM count was significantly higher than by one-field HLA typing. For additional typed HLA loci -DRB345, -DQA1, -DPA1, and -DPB1 we observed 2, 26, 3, and 23 MM, respectively. In total, 37.3% (69/185) of de novo donor specific antibodies (DSA) formation was directed against these loci (DRB345 ➔ n=33, DQA1 ➔ n=33, DPA1 ➔ n=1, DPB1 ➔ n=10).ConclusionOur results indicate that two-field HLA typing is feasible and provides significantly more sensitive HLA MM recognition in living-donor KT. Furthermore, accurate HLA typing plays an important role in graft management as it can improve discrimination between donor and non-donor HLA directed cellular and humoral alloreactivity in the long range. The inclusion of additional HLA loci against which antibodies can be readily detected, HLA-DRB345, -DQA1, -DQB1, -DPA1, and -DPB1, will allow a more precise virtual crossmatch and better prediction of potential DSA. Furthermore, in living KT, two-field HLA typing could contribute to the selection of the immunologically most suitable donors.

Background Healthcaare delivery will change through the increasing use of artificial intelligence (AI). Physicians are likely to be among the professions most affected, though to what extent is not yet clear. Objective We analyzed physicians’ and AI experts’ stances towards AI-induced changes. This concerned (1) physicians’ tasks, (2) job replacement risk, and (3) implications for the ways of working, including human–AI interaction, changes in job profiles, and hierarchical and cross-professional collaboration patterns. Methods We adopted an exploratory, qualitative research approach, using semi-structured interviews with 24 experts in the fields of AI and medicine, medical informatics, digital medicine, and medical education and training. Thematic analysis of the interview transcripts was performed. Results Specialized tasks currently performed by physicians in all areas of medicine would likely be taken over by AI, including bureaucratic tasks, clinical decision support, and research. However, the concern that physicians will be replaced by an AI system is unfounded, according to experts; AI systems today would be designed only for a specific use case and could not replace the human factor in the patient–physician relationship. Nevertheless, the job profile and professional role of physicians would be transformed as a result of new forms of human–AI collaboration and shifts to higher-value activities. AI could spur novel, more interprofessional teams in medical practice and research and, eventually, democratization and de-hierarchization. Conclusions The study highlights changes in job profiles of physicians and outlines demands for new categories of medical professionals considering AI-induced changes of work. Physicians should redefine their self-image and assume more responsibility in the age of AI-supported medicine. There is a need for the development of scenarios and concepts for future job profiles in the health professions as well as their education and training.

IntroductionHumoral immunity after SARS-CoV-2 vaccination has been extensively investigated in blood. Aim of this study was to develop an ELISA method in order to determine the prevalence of IgG and IgA SARS-CoV-2 domain 1 spike-protein (S) specific antibodies (Abs) in buccal and nasal mucosal surfaces of vaccinees.MethodsTo this end, we analyzed 69 individuals who received their first vaccine dose between February and July 2021. Vaccines administered were BNT162b2, mRNA-1273 or ChAdOx1-nCoV-19. Detection of IgG and IgA Abs was performed using commercial ELISA kits for both blood and swab samples after protocol modification for the latter.ResultsAnti-spike IgG and IgA Abs in the buccal and/or nasal swabs were detectable in >81% of the study subjects after the second dose. The IgG measurements in buccal swabs appeared to correlate in a more consistent way with the respective measurements in blood with a correlation coefficient of r=0.74. It is of note that IgA Abs appeared to be significantly more prevalent in the nasal compared to the buccal mucosa. Optimal selection of the assay cut-off for the IgG antibody detection in buccal swabs conferred a sensitivity of 91.8% and a specificity of 100%. Last, individuals vaccinated with mRNA-based vaccines exhibited higher antibody levels in both blood and mucosal surfaces compared to those receiving ChAdOx1-nCoV-19 confirming previously reported results.ConclusionIn conclusion, our findings show a differential prevalence of anti-S Abs on mucosal surfaces after vaccination for SARS-CoV-2, while they also set the basis for potential future use of IgG antibody detection in buccal swabs for extended immunity screening in large populations.

ObjectivesTo determine the profile of cytokines in patients with severe COVID-19 who were enrolled in a trial of COVID-19 convalescent plasma (CCP).MethodsPatients were randomized to receive standard treatment and 3 CCP units or standard treatment alone (CAPSID trial, ClinicalTrials.gov NCT04433910). The primary outcome was a dichotomous composite outcome (survival and no longer severe COVID-19 on day 21). Time to clinical improvement was a key secondary endpoint. The concentrations of 27 cytokines were measured (baseline, day 7). We analyzed the change and the correlation between serum cytokine levels over time in different subgroups and the prediction of outcome in receiver operating characteristics (ROC) analyses and in multivariate models.ResultsThe majority of cytokines showed significant changes from baseline to day 7. Some were strongly correlated amongst each other (at baseline the cluster IL-1ß, IL-2, IL-6, IL-8, G-CSF, MIP-1α, the cluster PDGF-BB, RANTES or the cluster IL-4, IL-17, Eotaxin, bFGF, TNF-α). The correlation matrix substantially changed from baseline to day 7. The heatmaps of the absolute values of the correlation matrix indicated an association of CCP treatment and clinical outcome with the cytokine pattern. Low levels of IP-10, IFN-γ, MCP-1 and IL-1ß on day 0 were predictive of treatment success in a ROC analysis. In multivariate models, low levels of IL-1ß, IFN-γ and MCP-1 on day 0 were significantly associated with both treatment success and shorter time to clinical improvement. Low levels of IP-10, IL-1RA, IL-6, MCP-1 and IFN-γ on day 7 and high levels of IL-9, PDGF and RANTES on day 7 were predictive of treatment success in ROC analyses. Low levels of IP-10, MCP-1 and high levels of RANTES, on day 7 were associated with both treatment success and shorter time to clinical improvement in multivariate models.ConclusionThis analysis demonstrates a considerable dynamic of cytokines over time, which is influenced by both treatment and clinical course of COVID-19. Levels of IL-1ß and MCP-1 at baseline and MCP-1, IP-10 and RANTES on day 7 were associated with a favorable outcome across several endpoints. These cytokines should be included in future trials for further evaluation as predictive factors.

BackgroundThe role of telemedicine in intensive care has been increasing steadily. Tele–intensive care unit (ICU) interventions are varied and can be used in different levels of treatment, often with direct implications for the intensive care processes. Although a substantial body of primary and secondary literature has been published on the topic, there is a need for broadening the understanding of the organizational factors influencing the effectiveness of telemedical interventions in the ICU. ObjectiveThis scoping review aims to provide a map of existing evidence on tele-ICU interventions, focusing on the analysis of the implementation context and identifying areas for further technological research. MethodsA research protocol outlining the method has been published in JMIR Research Protocols. This review follows the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews). A core research team was assembled to provide feedback and discuss findings. ResultsA total of 3019 results were retrieved. After screening, 25 studies were included in the final analysis. We were able to characterize the context of tele-ICU studies and identify three use cases for tele-ICU interventions. The first use case is extending coverage, which describes interventions aimed at extending the availability of intensive care capabilities. The second use case is improving compliance, which includes interventions targeted at improving patient safety, intensive care best practices, and quality of care. The third use case, facilitating transfer, describes telemedicine interventions targeted toward the management of patient transfers to or from the ICU. ConclusionsThe benefits of tele-ICU interventions have been well documented for centralized systems aimed at extending critical care capabilities in a community setting and improving care compliance in tertiary hospitals. No strong evidence has been found on the reduction of patient transfers following tele-ICU intervention. International Registered Report Identifier (IRRID)RR2-10.2196/19695

BackgroundArtificial intelligence (AI) holds the promise of supporting nurses’ clinical decision-making in complex care situations or conducting tasks that are remote from direct patient interaction, such as documentation processes. There has been an increase in the research and development of AI applications for nursing care, but there is a persistent lack of an extensive overview covering the evidence base for promising application scenarios. ObjectiveThis study synthesizes literature on application scenarios for AI in nursing care settings as well as highlights adjacent aspects in the ethical, legal, and social discourse surrounding the application of AI in nursing care. MethodsFollowing a rapid review design, PubMed, CINAHL, Association for Computing Machinery Digital Library, Institute of Electrical and Electronics Engineers Xplore, Digital Bibliography & Library Project, and Association for Information Systems Library, as well as the libraries of leading AI conferences, were searched in June 2020. Publications of original quantitative and qualitative research, systematic reviews, discussion papers, and essays on the ethical, legal, and social implications published in English were included. Eligible studies were analyzed on the basis of predetermined selection criteria. ResultsThe titles and abstracts of 7016 publications and 704 full texts were screened, and 292 publications were included. Hospitals were the most prominent study setting, followed by independent living at home; fewer application scenarios were identified for nursing homes or home care. Most studies used machine learning algorithms, whereas expert or hybrid systems were entailed in less than every 10th publication. The application context of focusing on image and signal processing with tracking, monitoring, or the classification of activity and health followed by care coordination and communication, as well as fall detection, was the main purpose of AI applications. Few studies have reported the effects of AI applications on clinical or organizational outcomes, lacking particularly in data gathered outside laboratory conditions. In addition to technological requirements, the reporting and inclusion of certain requirements capture more overarching topics, such as data privacy, safety, and technology acceptance. Ethical, legal, and social implications reflect the discourse on technology use in health care but have mostly not been discussed in meaningful and potentially encompassing detail. ConclusionsThe results highlight the potential for the application of AI systems in different nursing care settings. Considering the lack of findings on the effectiveness and application of AI systems in real-world scenarios, future research should reflect on a more nursing care–specific perspective toward objectives, outcomes, and benefits. We identify that, crucially, an advancement in technological-societal discourse that surrounds the ethical and legal implications of AI applications in nursing care is a necessary next step. Further, we outline the need for greater participation among all of the stakeholders involved.

Abstract Background Especially patients older than 65 years undergoing surgery are prone to develop frailty-related complications that may go far beyond the index hospitalization (e.g., cognitive impairment following postoperative delirium). However, aging-relevant information are currently not fully integrated into hospitals’ perioperative processes. Methods We introduce a temporal perspective, which focuses on the social construction of time, to better understand existing barriers to the exchange of frailty-related data, targeting complexity research. Our chosen context is perioperative care provided by a tertiary hospital in Germany that has implemented a special track for patients over 65 years old undergoing elective surgery. The research followed a participatory modelling approach between domain and modelling experts with the goal of creating a feedback loop model of the relevant system relationships and dynamics. Results The results of the study show how disparate temporal regimes, understood as frameworks for organizing actions in the light of time constraints, time pressure, and deadlines, across different clinical, ambulant, and geriatric care sectors create disincentives to cooperate in frailty-related data exchanges. Moreover, we find that shifting baselines, meaning continuous increases in cost and time pressure in individual sectors, may unintentionally reinforce – rather than discourage – disparate temporal regimes. Conclusions Together, these results may (1) help to increase awareness of the importance of frailty-related data exchanges, and (2) impel efforts aiming to transform treatment processes to go beyond sectoral boundaries, taking into account the potential benefits for frail patients arising from integrated care processes using information technology.

Abstract Theories of path dependence and incumbent inertia assume that self-reinforcing mechanisms lead to highly persistent and eventually inefficient institutional solutions. The resulting lock-in is likely to threaten the viability of an organization. While path dependence theory was initially developed as a market-based approach, it has more recently been transferred to institutional settings and in particular to hierarchies. Some critics doubt, however, its applicability to hierarchical organizations. The major argument states that asymmetric power structures in organizations differ significantly from symmetric coordination modes and autonomous evolutionary dynamics. Hierarchical authority is assumed to be stronger and to rule out emergent autonomous dynamics. This reasoning raises the question whether hierarchical structures are actually strong enough to suppress (deliberately) the power of evolutionary self-reinforcing organizational dynamics, or vice versa. To our knowledge, there are no studies to date examining in detail these reverse dynamics. In this paper, we build on simulations to study these competing dynamics and possible conditions that favor one view or the other. We suggest using agent-based simulation and modeling, conceiving of institutional change as an interdependent multi-level process that can be analyzed numerically. The results indicate that in most situations self-reinforcing organizational dynamics can actually overrule hierarchical authority, whilst in some other situations formal authority proves to be stronger.

The differentiation of human induced pluripotent stem cells (hiPSCs) into T and natural killer (NK) lymphocytes opens novel possibilities for developmental studies of immune cells and in-vitro generation of cell therapy products. In particular, iPSC-derived NK cells gained interest in adoptive anti-cancer immunotherapies, since they enable generation of homogenous populations of NK cells with and without genetic engineering that can be grown at clinical scale. However, the phenotype of in-vitro generated NK cells is not well characterized. NK cells derive in the bone marrow and mature in secondary lymphoid tissues through distinct stages from CD56brightCD16- to CD56dimCD16+ NK cells that represents the most abandoned population in peripheral blood. In this study, we efficiently generated CD56+CD16+CD3- NK lymphocytes from hiPSC and characterized NK-cell development by surface expression of NK-lineage markers. Hematopoietic priming of hiPSC resulted in 31.9% to 57.4% CD34+CD45+ hematopoietic progenitor cells (HPC) that did not require enrichment for NK lymphocyte propagation. HPC were further differentiated into NK cells on OP9-DL1 feeder cells resulting in high purity of CD56brightCD16- and CD56brightCD16+ NK cells. The output of generated NK cells increased up to 40% when OP9-DL1 feeder cells were inactivated with mitomycine C. CD7 expression could be detected from the first week of differentiation indicating priming towards the lymphoid lineage. CD56brightCD16-/+ NK cells expressed high levels of DNAM-1, CD69, natural killer cell receptors NKG2A and NKG2D, and natural cytotoxicity receptors NKp46, NKp44, NKp30. Expression of NKp80 on 40% of NK cells, and a perforin+ and granzyme B+ phenotype confirmed differentiation up to stage 4b. Killer cell immunoglobulin-like receptor KIR2DL2/DL3 and KIR3DL1 were found on up to 3 and 10% of mature NK cells, respectively. NK cells were functional in terms of cytotoxicity, degranulation and antibody-dependent cell-mediated cytotoxicity.

MICA and MICB are ligands of the NKG2D receptor and thereby influence NK and T cell activity. MICA/B gene polymorphisms, expression levels and the amount of soluble MICA/B in the serum have been linked to autoimmune diseases, infections, and cancer. In hematopoietic stem cell transplantation, MICA matching between donor and patient has been correlated with reduced acute and chronic graft-vs.-host disease and improved survival. Hence, we developed an extremely cost-efficient high-throughput workflow for genotyping MICA/B for newly registered potential stem cell donors. Since mid-2017, we have genotyped over two million samples using NGS amplicon sequencing for MICA/B exons 2–5. In donors of German origin, MICA*008 is the most common MICA allele with a frequency of 42.3%. It is followed by MICA*002 (11.7%) and MICA*009 (8.8%). The three most common MICB alleles are MICB*005 (43.9%), MICB*004 (21.7%), and MICB*002 (18.9%). In general, MICB is less diverse than MICA and only 6 alleles, instead of 15, account for a cumulative allele frequency of 99.5%. In 0.5% of the samples we observed at least one allele of MICA or MICB which has so far not been reported to the IPD/IMGT-HLA database. By providing MICA/B typed voluntary donors, clinicians become empowered to include MICA/B into their donor selection process to further improve unrelated hematopoietic stem cell transplantation.

The US national mortality rates from systemic sclerosis (SSc) have not been reported since 1979. We studied age, gender and race specific time trends in US national mortality rates of SSc during the period 1979–1998 using poisson regression models. Over the 4.93 billion person-years of observation during the study period, there were 18,126 deaths from SSc, representing a mortality rate of 3.9 per million. The age adjusted mortality rates for men and women were 1.9 and 5.4 per million respectively. There were relatively few deaths in the extremes of age. SSc mortality rates increased with age in both genders and in all racial groups (p<0.001). In multivariable models adjusted for two-way statistical interactions, being African–American, female and of older age were associated with higher death rates. Over the 20 years of observation, overall (age-adjusted) SSc mortality rates showed a 36% increase (p<0.001) and subgroup analyses revealed that the increases were confined to women of both races. This rise occurred during a period in which post-diagnosis survival of SSc is known to have increased, suggesting an increasing incidence of this disease. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) enters cells through the reduced folate carrier (RFC?1) and exerts part of its effects through polyglutamation to MTX polyglutamates (MTXPGs) and inhibition of 5?aminoimidazole?4?carboxamide ribonucleotide transformylase (ATIC) and thymidylate synthase (TS). We investigated the contribution of common genetic polymorphisms in RFC?1 (G80A), ATIC (C347G), and TS (28?bp tandem repeats located in the TS enhancer region [TSER*2/*3]) and of MTXPGs to the effect of MTX in patients with rheumatoid arthritis.The study was cross?sectional. All patients received MTX for at least 3 months. The numbers of tender and swollen joints, the Visual Analog Scale (VAS) scores for the physician''s global assessment of disease activity, and the modified Health Assessment Questionnaire scores were collected. Using the VAS score for the physician''s assessment of patient''s response to MTX, the population of patients was dichotomized into responders to MTX (VAS score ?2 cm) and nonresponders to MTX (VAS score >2 cm). A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC?1 AA + ATIC 347GG + TSER *2/*2) carried by the patients. MTXPG concentrations were measured in red blood cells (RBCs) by high?performance liquid chromatography.The dose of MTX was not associated with the effects of MTX (P > 0.05). In contrast, increased RBC long?chain MTXPG concentrations (median 40 nmoles/liter; range <5–131 nmoles/liter) and an increased pharmacogenetic index were associated with a lower number of tender and swollen joints (P < 0.05) and a lower score for the physician''s global assessment of disease activity (P ? 0.001). Patients with RBC MTXPG levels of >60 nmoles/liter and carriers of a homozygous variant genotype were 14.0?fold (95% confidence interval [95% CI] 3.6–53.8) and 3.7?fold (95% CI 1.7–9.1), respectively, more likely to have a good response to MTX (P ? 0.01).These data suggest that measuring RBC MTXPG levels and/or the common polymorphisms in the folate–purine–pyrimidine pathway may help in monitoring MTX therapy. [ABSTRACT FROM AUTHOR]

Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion.

The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs. 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48–0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs. 18%, P=0.005; HR=0.40, CI 95%=0.22–0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post–transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.

We investigated a possible interaction between age-associated risk and HLA-mismatch associated risk on prognosis in different age categories of recipients of unrelated hematopoietic stem cell transplants (HSCT) (n=3019). Patients over 55 years of age transplanted with 8/10 donors showed a mortality risk of 2.27 (CI 1.70–3.03, P

Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.

The estimated frequency of MSCs in BM is about 0.001–0.01% of total nucleated cells. Most commonly, one applied therapeutic cell dose is about 1–5 million MSCs/kg body weight, necessitating a reliable, fast, and safe expansion system. The limited availability of MSCs demands for an extensive ex vivo amplification step to accumulate sufficient cell numbers. Human platelet lysate (PL) has proven to be a safe and feasible alternative to animal-derived serum as supplement for MSC cultivation. We have investigated the functionally closed automated cell culture hollow fiber bioreactor Quantum cell expansion system as an alternative novel tool to conventional tissue flasks for efficient clinical-scale MSC isolation and expansion from bone marrow using PL. Cells expanded in the Quantum system fulfilled MSC criteria as shown by flow cytometry and adipogenic, chondrogenic, and osteogenic differentiation capacity. Cell surface expression of a variety of chemokine receptors, adhesion molecules, and additional MSC markers was monitored for several passages by flow cytometry. The levels of critical media components like glucose and lactate were analyzed. PDGF-AA, PDGF-AB/BB, bFGF, TGF-β1, sICAM-1, sVCAM-1, RANTES, GRO, VEGF, sCD40L, and IL-6 were assessed using a LUMINEX platform. Originally optimized for the use of fetal calf serum (FCS) as supplement and fibronectin as coating reagent, we succeeded to obtain an average of more than 100 × 10 6 of MSCs from as little as 18.8–28.6 ml of BM aspirate using PL. We obtained similar yields of MSCs/μl BM in the FCS-containing and the xenogen-free expansion system. The Quantum system reliably produces a cellular therapeutic dose in a functionally closed system that requires minimal manipulation. Both isolation and expansion are possible using FCS or PL as supplement. Coating of the hollow fibers of the bioreactor is mandatory when loading MSCs. Fibronectin, PL, and human plasma may serve as coating reagents.

BACKGROUND: Mesenchymal stromal cells (MSC) have gained importance in tissue repair, tissue engineering and in immunosupressive therapy during the last years. Due to the limited availability of MSC in the bone marrow, ex vivo amplification prior to clinical application is requisite to obtain therapeutic applicable cell doses. Translation of preclinical into clinical-grade large-scale MSC expansion necessitates precise definition and standardization of all procedural parameters including cell seeding density, culture medium and cultivation devices. While xenogeneic additives such as fetal calf serum are still widely used for cell culture, its use in the clinical context is associated with many risks, such as prion and viral transmission or adverse immunological reactions against xenogeneic components. METHODS AND FINDINGS: We established animal-free expansion protocols using platelet lysate as medium supplement and thereby could confirm its safety and feasibility for large-scale MSC isolation and expansion. Five different GMP-compliant standardized protocols designed for the safe, reliable, efficient and economical isolation and expansion of MSC was performed and MSC obtained were analyzed for differentiation capacity by qPCR and histochemistry. Expression of standard MSC markers as defined by the International Society for Cellular Therapy as well as expression of additional MSC markers and of various chemokine and cytokine receptors was analysed by flow cytometry. Changes of metabolic markers and cytokines in the medium were addressed using the LUMINEX platform. CONCLUSIONS: The five different systems for isolation and expansion of MSC described in this study are all suitable to produce at least 100 millions of MSC, which is commonly regarded as a single clinical dose. Final products are equal according to the minimal criteria for MSC defined by the ISCT. We showed that chemokine and integrin receptors analyzed had the same expression pattern, suggesting that MSC from either of the systems show equal characteristics of homing and adhesion.

Objective: Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV. Methods: Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV. Results: Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews. Conclusion: Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis.

The Disease Activity Score (DAS) is widely used in clinical trials. A DAS of 5.1 defines the level of severe rheumatoid arthritis (RA) and is the criterion for the initiation of anti–tumor necrosis factor therapy in the UK and The Netherlands. In North America, similar rules are sometimes imposed. However, it is not known how accurately the DAS characterizes RA activity. The present study was undertaken to determine the concordance between DAS scores and physicians' assessments of RA activity, to investigate factors relating to discrepancies, and to assess the suitability of using the DAS in individual patients.Six hundred sixty‐nine RA patients were assessed using the DAS and other clinical measures. A physician's global estimate of RA activity was performed using an 11‐point predefined scale and a standard definition of disease activity.The DAS and physician global assessment had substantially different distributions of values. The level of agreement (Kendall's tau‐a) between DAS scores and physician global assessments was 49% (95% confidence interval 45–53%), Lin's coefficient of concordance was 0.62, and the Bland‐Altman 95% limits of agreement were −3.17 and 3.99. These results suggest poor‐to‐moderate concordance between the 2 measures of disease activity.The DAS and the physician's assessment of RA activity do not approach, value, and weight RA variables to the same extent, suggesting that RA activity is not evaluated similarly by North American physicians and with the DAS. The scales do not have acceptable levels of concordance. There is too much inherent variability in the DAS and other RA scales (e.g., the Health Assessment Questionnaire) to recommend them as sole determinants of RA activity for clinical or regulatory purposes. [ABSTRACT FROM AUTHOR]