Postoperative complications and mortality after major gastrointestinal surgery

Background and objective: The incidence of postoperative complications and death is low in the general population, but a subgroup of high-risk patients can be identified amongst whom adverse postoperative outcomes occur more frequently. The present study was undertaken to describe the incidence of postoperative complications, length of stay, and mortality after major abdominal surgery for gastrointestinal, hepatobiliary and pancreatic malignancies and to identify the risk factors for impaired outcome. Material and methods: Data of patients, operated on for gastro-intestinal malignancies during 2009–2010 were retrieved from the clinical database of Tartu University Hospital. Major outcome data included incidence of postoperative complications, hospital-, 30-day, 90-day and 1-year mortality, and length of ICU and hospital stay. High-risk patients were defined as patients with American Society of Anesthesiologists (ASA) physical status ≥3 and revised cardiac risk index (RCRI) ≥3. Multivariate analysis was used to determine the risk factors for postoperative mortality and morbidity. Results: A total of 507 (259 men and 248 women, mean age 68.3 ± 11.3 years) were operated on for gastrointestinal, hepatobiliary, or pancreatic malignancies during 2009 and 2010 in Tartu University Hospital, Department of Surgical Oncology. 25% of the patients were classified as high risk patients. The lengths of intensive care and hospital stay were 4.4 ± 7 and 14.5 ± 10 days, respectively. The rate of postoperative complications was 33.5% in the total cohort, and 44% in high-risk patients. The most common complication was delirium, which occurred in 12.8% of patients. For patients without high risk (ASA < III; RCRI < 3) in-hospital, 30-, 90-day and 1-year mortality were 2%, 5%, 12.7% and 26.0%. Patients with ASA ≥ III and RCRI ≥ 3 had 2.3% in-hospital mortality, and at 30-, 90 days and 1 year the mortality was 8.5%, 17.8%, and 42.2%, respectively (P = 0.001, P < 0.0001 and P < 0.0001 compared to the lower risk patients). On multivariate analysis, age above 70 years, ASA ≥ III, RCRI ≥ 3, duration of surgery >130 min, and positive fluid balance >1300 mL after the 1st postoperative day, were identified as independent risk factors for the development of complications. Conclusion: The complication rate after major gastro-intestinal surgery is high. ASA physical status and revised cardiac risk index adequately reflect increased risk for postoperative complications and worse short and long-term outcome

Forms of Understanding of XAI-Explanations

Explainability has become an important topic in computer science and artificial intelligence, leading to a subfield called Explainable Artificial Intelligence (XAI). The goal of providing or seeking explanations is to achieve (better) 'understanding' on the part of the explainee. However, what it means to 'understand' is still not clearly defined, and the concept itself is rarely the subject of scientific investigation. This conceptual article aims to present a model of forms of understanding in the context of XAI and beyond. From an interdisciplinary perspective bringing together computer science, linguistics, sociology, and psychology, a definition of understanding and its forms, assessment, and dynamics during the process of giving everyday explanations are explored. Two types of understanding are considered as possible outcomes of explanations, namely enabledness, 'knowing how' to do or decide something, and comprehension, 'knowing that' -- both in different degrees (from shallow to deep). Explanations regularly start with shallow understanding in a specific domain and can lead to deep comprehension and enabledness of the explanandum, which we see as a prerequisite for human users to gain agency. In this process, the increase of comprehension and enabledness are highly interdependent. Against the background of this systematization, special challenges of understanding in XAI are discussed

Explanation as a Social Practice: Toward a Conceptual Framework for the Social Design of AI Systems

none20siThe recent surge of interest in explainability in artificial intelligence (XAI) is propelled by not only technological advancements in machine learning, but also by regulatory initiatives to foster transparency in algorithmic decision making. In this article, we revise the current concept of explainability and identify three limitations: passive explainee, narrow view on the social process, and undifferentiated assessment of understanding. In order to overcome these limitations, we present explanation as a social practice in which explainer and explainee co-construct understanding on the microlevel. We view the co-construction on a microlevel as embedded into a macrolevel, yielding expectations concerning, e.g., social roles or partner models: Typically, the role of the explainer is to provide an explanation and to adapt it to the current level of understanding of the explainee; the explainee, in turn, is expected to provide cues that guide the explainer. Building on explanations being a social practice, we present a conceptual framework that aims to guide future research in XAI. The framework relies on the key concepts of monitoring and scaffolding to capture the development of interaction. We relate our conceptual framework and our new perspective on explaining to transparency and autonomy as objectives considered for XAInoneKatharina J. Rohlfing; Philipp Cimiano; Ingrid Scharlau; Tobias Matzner; Heike M. Buhl; Hendrik Buschmeier; Elena Esposito; Angela Grimminger; Barbara Hammer; Reinhold Häb-Umbach; Ilona Horwath; Eyke Hüllermeier; Friederike Kern; Stefan Kopp; Kirsten Thommes; Axel-Cyrille Ngonga Ngomo; Carsten Schulte; Henning Wachsmuth; Petra Wagner; Britta WredeKatharina J. Rohlfing; Philipp Cimiano; Ingrid Scharlau; Tobias Matzner; Heike M. Buhl; Hendrik Buschmeier; Elena Esposito; Angela Grimminger; Barbara Hammer; Reinhold Häb-Umbach; Ilona Horwath; Eyke Hüllermeier; Friederike Kern; Stefan Kopp; Kirsten Thommes; Axel-Cyrille Ngonga Ngomo; Carsten Schulte; Henning Wachsmuth; Petra Wagner; Britta Wred

Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants.

The origin of SARS-CoV-2 variants of concern remains unclear. Here, we test whether intra-host virus evolution during persistent infections could be a contributing factor by characterizing the long-term SARS-CoV-2 infection dynamics in an immunosuppressed kidney transplant recipient. Applying RT-qPCR and next-generation sequencing (NGS) of sequential respiratory specimens, we identify several mutations in the viral genome late in infection. We demonstrate that a late viral isolate exhibiting genome mutations similar to those found in variants of concern first identified in UK, South Africa, and Brazil, can escape neutralization by COVID-19 antisera. Moreover, infection of susceptible mice with this patient's escape variant elicits protective immunity against re-infection with either the parental virus and the escape variant, as well as high neutralization titers against the alpha and beta SARS-CoV-2 variants, B.1.1.7 and B.1.351, demonstrating a considerable immune control against such variants of concern. Upon lowering immunosuppressive treatment, the patient generated spike-specific neutralizing antibodies and resolved the infection. Our results suggest that immunocompromised patients could be a source for the emergence of potentially harmful SARS-CoV-2 variants

Characterization of genome-wide p53-binding sites upon stress response

The tumor suppressor p53 is a sequence-specific transcription factor, which regulates the expression of target genes involved in different stress responses. To understand p53's essential transcriptional functions, unbiased analysis of its DNA-binding repertoire is pivotal. In a genome-wide tiling ChIP-on-chip approach, we have identified and characterized 1546 binding sites of p53 upon Actinomycin D treatment. Among those binding sites were known as well as novel p53 target sites, which included regulatory regions of potentially novel transcripts. Using this collection of genome-wide binding sites, a new high-confidence algorithm was developed, p53scan, to identify the p53 consensus-binding motif. Strikingly, this motif was present in the majority of all bound sequences with 83% of all binding sites containing the motif. In the surrounding sequences of the binding sites, several motifs for potential regulatory cobinders were identified. Finally, we show that the majority of the genome-wide p53 target sites can also be bound by overexpressed p63 and p73 in vivo, suggesting that they can possibly play an important role at p53 binding sites. This emphasizes the possible interplay of p53 and its family members in the context of target gene binding. Our study greatly expands the known, experimentally validated p53 binding site repertoire and serves as a valuable knowledgebase for future research

Physician and Patient Predictors of Evidence-Based Prescribing in Heart Failure: A Multilevel Study

BACKGROUND: The management of patients with heart failure (HF) needs to account for changeable and complex individual clinical characteristics. The use of renin angiotensin system inhibitors (RAAS-I) to target doses is recommended by guidelines. But physicians seemingly do not sufficiently follow this recommendation, while little is known about the physician and patient predictors of adherence. METHODS: To examine the coherence of primary care (PC) physicians' knowledge and self-perceived competencies regarding RAAS-I with their respective prescribing behavior being related to patient-associated barriers. Cross-sectional follow-up study after a randomized medical educational intervention trial with a seven month observation period. PC physicians (n = 37) and patients with systolic HF (n = 168) from practices in Baden-Wuerttemberg. Measurements were knowledge (blueprint-based multiple choice test), self-perceived competencies (questionnaire on global confidence in the therapy and on frequency of use of RAAS-I), and patient variables (age, gender, NYHA functional status, blood pressure, potassium level, renal function). Prescribing was collected from the trials' documentation. The target variable consisted of ≥50% of recommended RAAS-I dosage being investigated by two-level logistic regression models. RESULTS: Patients (69% male, mean age 68.8 years) showed symptomatic and objectified left ventricular (NYHA II vs. III/IV: 51% vs. 49% and mean LVEF 33.3%) and renal (GFR<50%: 22%) impairment. Mean percentage of RAAS-I target dose was 47%, 59% of patients receiving ≥50%. Determinants of improved prescribing of RAAS-I were patient age (OR 0.95, CI 0.92-0.99, p = 0.01), physician's global self-confidence at follow-up (OR 1.09, CI 1.02-1.05, p = 0.01) and NYHA class (II vs. III/IV) (OR 0.63, CI 0.38-1.05, p = 0.08). CONCLUSIONS: A change in physician's confidence as a predictor of RAAS-I dose increase is a new finding that might reflect an intervention effect of improved physicians' intention and that might foster novel strategies to improve safe evidence-based prescribing. These should include targeting knowledge, attitudes and skills

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues