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

Classical meets malignant hematology: a case of acquired εγδβ-thalassemia in clonal hematopoiesis

Hemoglobinopathies including thalassemias are among the most frequent genetic disorders worldwide. Primarily, these entities result from germline variants in the globin gene clusters and their cis-acting regulatory elements, and thus the WHO classifies thalassemias as inherited diseases. Non-inherited disorders of globin chain synthesis mimicking the phenotype of thalassemias have also been described and are referred to as acquired thalassemias. These forms mainly affect the alpha-globin genes and are observed at much lower frequencies..

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

Automated Non-Sterile Pharmacy Compounding: A Multi-Site Study in European Hospital and Community Pharmacies with Pediatric Immediate Release Propranolol Hydrochloride Tablets

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years