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Anemia is a common complication of chronic kidney disease, affecting the quality of life of patients. Among various factors, such as iron and erythropoietin deficiency, reduced red blood cell (RBC) lifespan has been implicated in the pathogenesis of anemia. However, mechanistic data on in vivo RBC dysfunction in kidney disease are lacking. Herein, we describe the development of chronic kidney disease-associated anemia in mice with proteinuric kidney disease resulting from either administration of doxorubicin or an inducible podocin deficiency. In both experimental models, anemia manifested at day 10 and progressed at day 30 despite increased circulating erythropoietin levels and erythropoiesis in the bone marrow and spleen. Circulating RBCs in both mouse models displayed altered morphology and diminished osmotic-sensitive deformability together with increased phosphatidylserine externalization on the outer plasma membrane, a hallmark of RBC death. Fluorescence-labelling of RBCs at day 20 of mice with doxorubicin-induced kidney disease revealed premature clearance from the circulation. Metabolomic analyses of RBCs from both mouse models demonstrated temporal changes in redox recycling pathways and Lands’ cycle, a membrane lipid remodeling process. Anemic patients with proteinuric kidney disease had an increased proportion of circulating phosphatidylserine-positive RBCs. Thus, our observations suggest that reduced RBC lifespan, mediated by altered RBC metabolism, reduced RBC deformability, and enhanced cell death contribute to the development of anemia in proteinuric kidney disease.

Background The IgE- and IgG4-binding patterns of the major fish allergen parvalbumins are not clearly understood. IgE antibody-binding to parvalbumin from Asian seabass, Lat c 1.01, is implicated in up to 90 % of allergic reactions, although the region of IgE or IgG4 epitopes are unknown. In the present study, we characterized the specific IgE- and IgG4-binding regions of Lat c 1.01 using serum from pediatric and adult patients with clinically-confirmed fish allergy. Methods A comparative investigation of patient IgE- and IgG4-binding to recombinant Lat c 1.01 was performed by immunoblotting and indirect ELISA using serum from 15 children and eight adults with clinically confirmed IgE-mediated reactions to fish. The IgE- and IgG4-binding regions of Lat c 1.01 were determined by inhibition ELISA using seven overlapping peptides spanning the entire 102 amino acid sequence. Elucidated IgE-binding regions were modelled and compared to known antibody-binding regions of parvalbumins from five other fish species. Results Ninety five percent (22/23) patients demonstrated IgE-binding to rLat c 1.01, while fewer patients (10/15 children and 7/8 adults) demonstrated robust IgG4 binding when determined by immunoblots. IgE-binding for both cohorts was significantly higher compared to IgG4-binding by ELISA. All patients in this study presented individual IgE and IgG4 epitope-recognition profiles. In addition to these patient-specific antibody binding sites, general IgE epitopes were also identified at the C- and N-terminal regions of this major fish allergen. Conclusions and Clinical relevance Our findings demonstrate two specific IgE epitopes on parvalbumin from Asian seabass, while IgG4 binding is much lower and patient specific. This study highlights the importance of advancement in epitope analysis regardless of the age group for diagnostics and immunotherapies for fish allergy.

Over the past few years, there has been a boost in the use of commercial virtual assistants. Obviously, these proprietary tools are well-performing, however the functionality they offer is limited, users are ”vendor-locked”, while possible user privacy issues rise. In this paper we argue that low-cost, open hardware solutions may also perform well, given the proper setup. Specifically, we perform an initial assessment of a low-cost virtual agent employing the Rasa framework integrated into a Raspberry Pi 4. We set up three different architectures, discuss their capabilities and limitations and evaluate the dialogue system against three axes: assistant comprehension, task success and assistant usability. Our experiments show that our low-cost virtual assistant performs in a satisfactory manner, even when a small-sized training dataset is used.

Background The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an alternative to conventional transvenous ICD (TV-ICD) therapy to reduce lead complications. Objective To evaluate outcomes in channelopathy vs patients with structural heart disease in the EFFORTLESS-SICD Registry and with a previously reported TV-ICD meta-analysis in channnelopathies. Methods The EFFORTLESS registry includes 199 patients with channelopathies (Brugada syndrome 83, long QT syndrome 24, idiopathic ventricular fibrillation 78, others 14) and 786 patients with structural heart disease. Results Channelopathy patients were younger (39 ± 14 years vs 51 ± 17 years; P < .001) with left ventricular ejection fraction 59% ± 9% vs 41% ± 18% (P < .001). The complication rate (follow-up: 3.2 ± 1.5 years vs 3.0 ± 1.5 years) was similar: 13.6% vs 11.2% (P = .42). Appropriate shocks rates were 9.5% vs 10.8% (P = .70), with shocks for monomorphic ventricular tachycardia being 2.0% vs 6.9% (P < .02) and for polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF) 8.0% vs 5.7% (P = .30). Conversion effectiveness of VT/VF episodes was similar: 36 of 37 (97.3%) vs 151 of 155 (97.4%, P = .59). VT/VF storm event (2% vs 0.9%, P = .33) and lower inappropriate shock (IAS) (8.5% vs 12.5%, P = .12) rates were statistically similar between channelopathy and non-channelopathy patients, with 45.5% channelopathy vs 31.4% non-channelopathy patients managed with a conditional zone > 200 beats per minute (P = .0002). Annualized appropriate shock, IAS, and complication rates appear to be lower for the S-ICD vs meta-analysis TV-ICD patients, particularly lead complications. Conclusion EFFORTLESS demonstrates similar S-ICD efficacy and a nonsignificant, lower rate of IAS in channelopathy patients as compared to structural heart disease. Comparable IAS rates were achieved with the device programmed to higher rates for channelopathy patients., Graphical abstract

Summary Introduction Ruminants (cattle and sheep) with Mycobacterium avium (MAP)-induced paratuberculosis (ptb), the ruminant model of Crohn's disease (CD), exhibit pancreatic specific autoantibodies (PAB) against GP2 but not against CUZD1. Since anti-Saccharomyces cerevisiae antibodies (ASCAs) is a CD marker, we tested MAP-infected ptb ruminants for ASCA, and compared them with ruminants lacking evidence of anti-MAP serology or with ruminants, which were positive for anti-GP2 antibodies. Material and methods A total of 98 samples from ruminants (48 cattle and 50 sheep) were studied. IgG anti-MAP antibodies, and CD-related ASCA and anti-GP2 antibodies were tested by modified ELISAs. Results Nine cattle (18.75%) and 20 sheep (40%) were suffered from ptb. ASCA antibodies were present in 21/48 (43.7%) cattle and 10/50 (20%) sheep while anti-GP2 antibodies were present in 14/48 (29.2%) cattle, and 8/50 (16%) sheep. ASCA antibodies were more prevalent in anti-MAP antibody positive (14/29, 48.3%) than in anti-MAP negative ruminants (17/69, 24.6%, P = 0.022) and also in anti-GP2 antibody positive (13/23, 56.5%) than in anti-GP2 negative ruminants (18/75, 24%, P = 0.003). No association between ASCA and anti-MAP antibody concentrations were found (r = 0.159, P = 0.117). A significant association between ASCA and anti-GP2 antibody concentration were observed (r = 0.211 and P = 0.037). Conclusion ASCA are present in a significant proportion of ruminants with ptb and correlate with anti-GP2 antibody positivity, a finding further supporting the notion that Crohn's disease and ptb share common immunological mechanisms of antigen-driven loss of self-tolerance.

Introduction Morbidity after breast cancer surgery remains low with revision surgery below 5%. This retrospective monocentric study investigates whether new methods like neoadjuvant chemotherapy (nCT), oncoplastic surgery (OPS) or intraoperative radiotherapy (IORT) affect overall morbidity. In addition, we sought to determine a possible effect of morbidity on oncologic outcome. Methods Clinical Data from all breast cancer cases, operated at the OnkoZert”- certified Breast Health Center of the “Sisters of Charity Hospital” in Linz between 2011 and 2014, were evaluated. Age (≤/>70), nCT, IORT, surgical technique and histological subtypes were analyzed concerning their impact on morbidity. Overall survival (OS) and disease-free survival (DFS) were assessed by Kaplan-Meier estimates. Results 829 patients were included, 24% were older than 70y, 19% underwent oncoplasty, 5.5% immediate reconstruction, 17% of the invasive cancers were treated with nCT and 4.1% received IORT. One or more complications occurred in 83 patients (10%), while 62 patients (7.5%) underwent revision surgery. Univariate analysis showed that mastectomy and age >70 doubled the risk of surgical morbidity. Multivariate regression analysis identified age >70 as the only independent prognostic parameter for the occurrence of morbidity (OR: 2.42, 95% CI: 1.41–4.1, p = 0,00134). Morbidity was not associated with worse oncologic outcome in terms of OS or DFS. Summary In our patient collective, modern techniques such as nCT, OPS or IORT did not influence surgical morbidity rates. Those were only increased by patient's age. Additionally, surgical morbidity did not show any significant impact on OS and DFS.

Background Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial. Patients and methods Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB). Results Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%–100%] and NPV 92.3% [95% CI 79.1%–98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63–0.84]) and NET (AUC 0.726 [95% CI 0.60–0.85]). Conclusions The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting.

Ulvan, a sulfated polysaccharide extracted from the green seaweed genus Ulva, has bioactive properties including an immunomodulating capacity. The immunomodulatory capacity of ulvan from Ulva ohnoi, however, has not been assessed in detail. We depolymerised purified ulvan from U. ohnoi to obtain a range of molecular weight fractions (Mw 7, 9, 13, 21, 209 kDa), which were characterised by constituent sugar analysis, SEC-MALLS, and NMR. Ulvan fractions contained 48.8–54.7 mol% rhamnose, 32.5–35.9 mol% glucuronic acid, 4.5–7.3 mol% iduronic acid, and 3.3–5.6 mol% xylose. 1H and 13C NMR was consistent with hydrolysis occurring at the anomeric centre without further modification to the oligosaccharide structure. The in vitro immunomodulatory effect of ulvan fractions was quantified by measuring levels of inflammatory-mediating signalling molecules released from LPS-stimulated RAW264.7 murine macrophages. All ulvan fractions showed no toxicity on RAW264.7 cells at concentrations below 100 μg mL−1 over 48 h. Secreted interleukin-10 and prostaglandin E2 demonstrated an anti-inflammatory effect by higher molecular weight ulvan fractions at 100 μg mL−1. To a lesser extent, these fractions also enhanced the LPS-induced inflammation through minor increases of IL-1β and IL-6. This study confirms that ulvan from U. ohnoi has a mild in vitro immunomodulatory effect.