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In this paper we present a deep learning segmentation approach to classify and quantify the two most prevalent primary liver cancers - hepatocellular carcinoma and intrahepatic cholangiocarcinoma - from hematoxylin and eosin (H&E) stained whole slide images. While semantic segmentation of medical images typically requires costly pixel-level annotations by domain experts, there often exists additional information which is routinely obtained in clinical diagnostics but rarely utilized for model training. We propose to leverage such weak information from patient diagnoses by deriving complementary labels that indicate to which class a sample cannot belong to. To integrate these labels, we formulate a complementary loss for segmentation. Motivated by the medical application, we demonstrate for general segmentation tasks that including additional patches with solely weak complementary labels during model training can significantly improve the predictive performance and robustness of a model. On the task of diagnostic differentiation between hepatocellular carcinoma and intrahepatic cholangiocarcinoma, we achieve a balanced accuracy of 0.91 (CI 95%: 0.86-0.95) at case level for 165 hold-out patients. Furthermore, we also show that leveraging complementary labels improves the robustness of segmentation and increases performance at case level., (© 2024. The Author(s).)

Lithium-sulfur batteries have a high energy density but lack cycle stability to reach market maturity. This is mainly due to the polysulfide shuttle mechanism, i. e., the leaching of active material from the cathode into the electrolyte and subsequent side reactions. We demonstrate how to attenuate the polysulfide shuttle by magnetron sputtering molybdenum oxysulfide, manganese oxide, and chromium oxide onto microporous polypropylene separators. The morphology of the amorphous coatings was analyzed by SEM and XRD. Electrochemical cyclization quantified how these coatings improved Coulombic efficiency and cycle stability. These tests were conducted in half cells. We compare the different performances of the different coatings with the known chemical and adsorption properties of the respective coating materials., (© 2024 Wiley-VCH GmbH.)

The human pathogenic bacterium Clostridioides difficile produces two exotoxins TcdA and TcdB, which inactivate Rho GTPases thereby causing C. difficile-associated diseases (CDAD) including life-threatening pseudomembranous colitis. Hypervirulent strains produce additionally the binary actin ADP-ribosylating toxin CDT. These strains are hallmarked by more severe forms of CDAD and increased frequency and severity. Once in the cytosol, the toxins act as enzymes resulting in the typical clinical symptoms. Therefore, targeting and inactivation of the released toxins are of peculiar interest. Prompted by earlier findings that human α-defensin-1 neutralizes TcdB, we investigated the effects of the defensin on all three C. difficile toxins. Inhibition of TcdA, TcdB, and CDT was demonstrated by analyzing toxin-induced changes in cell morphology, substrate modification, and decrease in transepithelial electrical resistance. Application of α-defensin-1 protected cells and human intestinal organoids from the cytotoxic effects of TcdA, TcdB, CDT, and their combination which is attributed to a direct interaction between the toxins and α-defensin-1. In mice, the application of α-defensin-1 reduced the TcdA-induced damage of intestinal loops in vivo. In conclusion, human α-defensin-1 is a specific and potent inhibitor of the C. difficile toxins and a promising agent to develop novel therapeutic options against C. difficile infections., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals, Inc. on behalf of Federation of American Societies for Experimental Biology.)

Deep learning has recently gained popularity in digital pathology due to its high prediction quality. However, the medical domain requires explanation and insight for a better understanding beyond standard quantitative performance evaluation. Recently, many explanation methods have emerged. This work shows how heatmaps generated by these explanation methods allow to resolve common challenges encountered in deep learning-based digital histopathology analyses. We elaborate on biases which are typically inherent in histopathological image data. In the binary classification task of tumour tissue discrimination in publicly available haematoxylin-eosin-stained images of various tumour entities, we investigate three types of biases: (1) biases which affect the entire dataset, (2) biases which are by chance correlated with class labels and (3) sampling biases. While standard analyses focus on patch-level evaluation, we advocate pixel-wise heatmaps, which offer a more precise and versatile diagnostic instrument. This insight is shown to not only be helpful to detect but also to remove the effects of common hidden biases, which improves generalisation within and across datasets. For example, we could see a trend of improved area under the receiver operating characteristic (ROC) curve by 5% when reducing a labelling bias. Explanation techniques are thus demonstrated to be a helpful and highly relevant tool for the development and the deployment phases within the life cycle of real-world applications in digital pathology.

Background: The pathogenic effects of Clostridium difficile are primarily attributable to the production of the large protein toxins (C difficile toxins [Tcd]) A (TcdA) and B (TcdB). These toxins monoglucosylate Rho GTPases in the cytosol of host cells, causing destruction of the actin cytoskeleton with cytotoxic effects. Low human serum albumin (HSA) levels indicate a higher risk of acquiring and developing a severe C difficile infection (CDI) and are associated with recurrent and fatal disease., Methods: We used a combined approach based on docking simulation and biochemical analyses that were performed in vitro on purified proteins and in human epithelial colorectal adenocarcinoma cells (Caco-2), and in vivo on stem cell-derived human intestinal organoids and zebrafish embryos., Results: Our results show that HSA specifically binds via its domain II to TcdA and TcdB and thereby induces their autoproteolytic cleavage at physiological concentrations. This process impairs toxin internalization into the host cells and reduces the toxin-dependent glucosylation of Rho proteins., Conclusions: Our data provide evidence for a specific HSA-dependent self-defense mechanism against C difficile toxins and provide an explanation for the clinical correlation between CDI severity and hypoalbuminemia.

Binary enterotoxins Clostridium (C.) botulinum C2 toxin, C. perfringens iota toxin and C. difficile toxin CDT are composed of a transport (B) and a separate non-linked enzyme (A) component. Their B-components mediate endocytic uptake into mammalian cells and subsequently transport of the A-components from acidic endosomes into the cytosol, where the latter ADP-ribosylate G-actin resulting in cell rounding and cell death causing clinical symptoms. Protein folding enzymes, including Hsp90 and peptidyl-prolyl cis/trans isomerases facilitate transport of the A-components across endosomal membranes. Here, we identified Hsp70 as a novel host cell factor specifically interacting with A-components of C2, iota and CDT toxins to facilitate their transport into the cell cytosol. Pharmacological Hsp70-inhibition specifically prevented pH-dependent trans-membrane transport of A-components into the cytosol thereby protecting living cells and stem cell-derived human miniguts from intoxication. Thus, Hsp70-inhibition might lead to development of novel therapeutic strategies to treat diseases associated with bacterial ADP-ribosylating toxins.

Kyphoplasty is an established method in the treatment of osteoporotic spine fractures. In 10-15% of cases cement extravasation and leakage into veins occur. We report about the rare course of an extravasation. In 2008 an osteoporotic compression fracture of L(4) and L(5) in a 62-year-old female patient was treated by kyphoplasty. In the treated vertebra filling of an outgoing vein towards the proximal right side occurred. Postoperatively the patient was free of complaints (VAS preoperative 9/10, postoperative 1/10). In the chest X-ray a small asymptomatic filling of a lung vessel on the left side was present. The patient arrived as an emergency case 2.5 years later with decompensated heart failure. In the chest CT and angiography cement emboli in the lung were seen as well as a perforation of the pericardium with beginning tamponade. A thoracotomy was performed. Intraoperatively two 4 cm long sharp cement pieces were removed from the heart, which had perforated the right ventricle. Leakages were closed by suture. The patient survived the operation and was dismissed after 2 weeks of intensive care for rehabilitation and from there dismissed home. Six months later she had no more problems. When filling vertebra in several levels one must pay attention to introducing cement with a thick consistency, otherwise venous emboli and lung emboli may occur. These are as a rule asymptomatic, but may result in exceptional life-threatening complications.

Although intensive exercise protocols are commonly used in practical training and scientific studies, there is recently a great scientific discussion about "high intensity (interval) training" (HIT). New are the large amounts of studies and the more detailed knowledge about the physiological responses and adaptations to HIT in comparison to the classic high volume, low intensity endurance training. The present article summarizes the current knowledge about HIT in endurance exercise for clinical applications. In the first part, molecular and cellular adaptations to HIT are discussed in comparison to low intensity high volume training. Furthermore, studies are summarized which compare HIT vs. HVT in the field of prevention and rehabilitation. Terminally the differences in physiological stimuli of both training interventions are considered.

Purpose: Little is known whether information about eye conditions on the Internet is complete and accurate to support patient or layman decision making., Methods: Quality of content modules about age-related macular degeneration (AMD) was analyzed on 20 web sites. Content analysis covered 72 criteria in 11 groups. Each single criterion was rated with '1' or '0' (yes/no answer)., Results: The interrater reliability between two observers was almost perfect (kappa = 0.86). On average, 25.6% (+/-15.6) of the criteria were fulfilled. In the categories diagnostic procedures, therapy, preventive checkups, prevention and prognosis of AMD, only 12.7, 18.3, 20.0, 25.0 and 30.0%, respectively, of the required content was given., Conclusion: Our study shows, based upon the example of university eye hospitals, that the full potential to provide laymen with firsthand and up-to-date information has by far not yet been achieved. Further research is needed on how the Internet influences the communication between patient and ophthalmologist., ((c) 2009 S. Karger AG, Basel.)

Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150-200 mg/m(2)), thiotepa (10 mg/kg), melphalan (120 mg/m(2)) and OKT-3 (5 mg/day, day -5 to +14) and no posttransplant immunosuppression. Twenty nine patients (median age=42 (range, 21-59) years) have been transplanted with this regimen. Diagnosis were AML (n=16), ALL (n=7), NHL (n=3), MM (n=2) and CML (n=1). Patients were "high risk" with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6x10(6) (range, 3.4-17x10(6)) CD34+ cells/kg, 4.4x10(4) (range, 0.006-44x10(4)) CD3+ T cells/kg and 7.2x10(7) (range, 0.02-37.3x10(7)) CD56+ cells/kg. Donor-recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2-3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m(2) fludarabine, the dose was reduced to 150 mg/m(2). Engraftment was rapid with a median time to >500 granulocytes/microL of 12 (range, 10-21) days, >20,000 platelets/microL of 11 (range, 7-38) days and full donor chimerism after 2-4 weeks in all patients. Incidence of grade II-IV degrees GVHD was 48% with grade II degrees =10, III degrees =2 and IV degrees =2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n=1), mucormycosis (n=1), pneumonia (n=3) or GVHD (n=1). Overall survival is 9/29 patients (31%) with deaths due to infections (n=7), GVHD (n=1) and relapse (n=12) with a median follow-up of 241 days (range, 112-1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.