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Ten patients with constrictive pericarditis were studied echocardiographically with specific reference to inter-ventricular septal dynamics. Abnormal movement of the interventricular septum was present in 8 patients and consisted of flattening in systole and unusual posterior motion in diastole. The aetiology of this type of movement is at present unknown but may be related to restriction of normal cardiac rotational dynamics. The interventricular septum also showed diminished degree of thickening (mean 21-2%). The amplitude of excursion was generally at the upper limit of or greater than normal. Left ventricular posterior wall amplitude of excursion was normal. Flattening of left ventricular posterior wall diastolic movement was seen in 4 patients. Right ventricular end-diastolic dimension was slightly increased (1-2 to 1-7 cm/m2) in 5 of 8 patients with abnormal septal motion, but no haemodynamic evidence of diastolic volume overload was found. Posterior pericardial thickening was noted echocardiographically when posterior calcification was present. We conclude that the most common though non-specific feature of the echocardiogram in patients with constrictive pericarditis is abnormal septal motion. Flattening of left ventricular posterior wall diastolic movement, posterior pericardial thickening, and epicardial-pericardial separation may also occur. [ABSTRACT FROM PUBLISHER]

Presents a series of abstracts on various topics of economics published in the 1964 issue of the periodical 'Bulletin of the Oxford University Institute of Economics and Statistics,' vol. 26. Comparative study of financial development plans of some South Asian countries; Appraisal of an experiment in mixed enterprise in two financial holding companies in Italy.

The paradigm of Industry 5.0 pushes the transition from the traditional to a novel, smart, digital, and connected industry, where well-being is key to enhance productivity, optimize man-machine interaction and guarantee workers' safety. This work aims to conduct a systematic review of current methodologies for monitoring and analyzing physical and cognitive ergonomics. Three research questions are addressed: (1) which technologies are used to assess the physical and cognitive well-being of workers in the workplace, (2) how the acquired data are processed, and (3) what purpose this well-being is evaluated for. This way, individual factors within the holistic assessment of worker well-being are highlighted, and information is provided synthetically. The analysis was conducted following the PRISMA 2020 statement guidelines. From the sixty-five articles collected, the most adopted (1) technological solutions, (2) parameters, and (3) data analysis and processing were identified. Wearable inertial measurement units and RGB-D cameras are the most prevalent devices used for physical monitoring; in the cognitive ergonomics, and cardiac activity is the most adopted physiological parameter. Furthermore, insights on practical issues and future developments are provided. Future research should focus on developing multi-modal systems that combine these aspects with particular emphasis on their practical application in real industrial settings.

The presence of donor-specific antibodies (DSA) such as antibodies directed against donor class I human leucocyte antigen (e.g., HLA-A) is a major barrier to kidney transplant success. As a proof of concept, functionalized magnetic nanoparticles have been designed to eliminate DSA from saline, blood and plasma of healthy donors and sensitized patients. Specific HLA-A1 protein was covalently bound to functionalized cobalt nanoparticles (fNP), human serum albumin (HSA) as control. fNP were added to anti-HLA class I-spiked saline, spiked volunteers' whole blood, and to whole blood and plasma of sensitized patients ex vivo. Anti-HLA-A1 antibody levels were determined with Luminex technology. Antibodies' median fluorescent intensity (MFI) was defined as the primary outcome. Furthermore, the impact of fNP treatment on blood coagulation and cellular uptake was determined. Treatment with fNP reduced MFI by 97 ± 2% and by 94 ± 4% (p < 0.001 and p = 0.001) in spiked saline and whole blood, respectively. In six known sensitized anti-HLA-A1 positive patients, a reduction of 65 ± 26% (p = 0.002) in plasma and 65 ± 33% (p = 0.012) in whole blood was achieved. No impact on coagulation was observed. A minimal number of nanoparticles was detected in peripheral mononuclear blood cells. The study demonstrates-in a first step-the feasibility of anti-HLA antibody removal using fNP. These pilot data might pave the way for a new personalized DSA removal technology in the future., (© 2024. The Author(s).)

Background: We developed models for tumor segmentation to automate the assessment of total tumor volume (TTV) in patients with colorectal liver metastases (CRLM)., Methods: In this prospective cohort study, pre- and post-systemic treatment computed tomography (CT) scans of 259 patients with initially unresectable CRLM of the CAIRO5 trial (NCT02162563) were included. In total, 595 CT scans comprising 8,959 CRLM were divided into training (73%), validation (6.5%), and test sets (21%). Deep learning models were trained with ground truth segmentations of the liver and CRLM. TTV was calculated based on the CRLM segmentations. An external validation cohort was included, comprising 72 preoperative CT scans of patients with 112 resectable CRLM. Image segmentation evaluation metrics and intraclass correlation coefficient (ICC) were calculated., Results: In the test set (122 CT scans), the autosegmentation models showed a global Dice similarity coefficient (DSC) of 0.96 (liver) and 0.86 (CRLM). The corresponding median per-case DSC was 0.96 (interquartile range [IQR] 0.95-0.96) and 0.80 (IQR 0.67-0.87). For tumor segmentation, the intersection-over-union, precision, and recall were 0.75, 0.89, and 0.84, respectively. An excellent agreement was observed between the reference and automatically computed TTV for the test set (ICC 0.98) and external validation cohort (ICC 0.98). In the external validation, the global DSC was 0.82 and the median per-case DSC was 0.60 (IQR 0.29-0.76) for tumor segmentation., Conclusions: Deep learning autosegmentation models were able to segment the liver and CRLM automatically and accurately in patients with initially unresectable CRLM, enabling automatic TTV assessment in such patients., Relevance Statement: Automatic segmentation enables the assessment of total tumor volume in patients with colorectal liver metastases, with a high potential of decreasing radiologist's workload and increasing accuracy and consistency., Key Points: • Tumor response evaluation is time-consuming, manually performed, and ignores total tumor volume. • Automatic models can accurately segment tumors in patients with colorectal liver metastases. • Total tumor volume can be accurately calculated based on automatic segmentations., (© 2023. The Author(s).)

For patients with colorectal cancer liver metastases (CRLM), the genetic mutation status is important in treatment selection and prognostication for survival outcomes. This study aims to investigate the relationship between radiomics imaging features and the genetic mutation status (KRAS mutation versus no mutation) in a large multicenter dataset of patients with CRLM and validate these findings in an external dataset. Patients with initially unresectable CRLM treated with systemic therapy of the randomized controlled CAIRO5 trial (NCT02162563) were included. All CRLM were semi-automatically segmented in pre-treatment CT scans and radiomics features were calculated from these segmentations. Additionally, data from the Netherlands Cancer Institute (NKI) were used for external validation. A total of 255 patients from the CAIRO5 trial were included. Random Forest, Gradient Boosting, Gradient Boosting + LightGBM, and Ensemble machine-learning classifiers showed AUC scores of 0.77 (95%CI 0.62-0.92), 0.77 (95%CI 0.64-0.90), 0.72 (95%CI 0.57-0.87), and 0.86 (95%CI 0.76-0.95) in the internal test set. Validation of the models on the external dataset with 129 patients resulted in AUC scores of 0.47-0.56. Machine-learning models incorporating CT imaging features could identify the genetic mutation status in patients with CRLM with a good accuracy in the internal test set. However, in the external validation set, the models performed poorly. External validation of machine-learning models is crucial for the assessment of clinical applicability and should be mandatory in all future studies in the field of radiomics.

Background: Addressing intraoperative bleeding remains a significant challenge in the field of robotic surgery. This research endeavors to pioneer a groundbreaking solution utilizing convolutional neural networks (CNNs). The objective is to establish a system capable of forecasting instances of intraoperative bleeding during robot-assisted radical prostatectomy (RARP) and promptly notify the surgeon about bleeding risks., Methods: To achieve this, a multi-task learning (MTL) CNN was introduced, leveraging a modified version of the U-Net architecture. The aim was to categorize video input as either "absence of blood accumulation" (0) or "presence of blood accumulation" (1). To facilitate seamless interaction with the neural networks, the Bleeding Artificial Intelligence-based Detector (BLAIR) software was created using the Python Keras API and built upon the PyQT framework. A subsequent clinical assessment of BLAIR's efficacy was performed, comparing its bleeding identification performance against that of a urologist. Various perioperative variables were also gathered. For optimal MTL-CNN training parameterization, a multi-task loss function was adopted to enhance the accuracy of event detection by taking advantage of surgical tools' semantic segmentation. Additionally, the Multiple Correspondence Analysis (MCA) approach was employed to assess software performance., Results: The MTL-CNN demonstrated a remarkable event recognition accuracy of 90.63%. When evaluating BLAIR's predictive ability and its capacity to pre-warn surgeons of potential bleeding incidents, the density plot highlighted a striking similarity between BLAIR and human assessments. In fact, BLAIR exhibited a faster response. Notably, the MCA analysis revealed no discernible distinction between the software and human performance in accurately identifying instances of bleeding., Conclusion: The BLAIR software proved its competence by achieving over 90% accuracy in predicting bleeding events during RARP. This accomplishment underscores the potential of AI to assist surgeons during interventions. This study exemplifies the positive impact AI applications can have on surgical procedures.

Keratinocytes (KCs) form the outer epithelial barrier of the body, protecting against invading pathogens. Mice lacking the IL-17RA or both IL-17A and IL-17F develop spontaneous Staphylococcusaureus skin infections. We found a marked expansion of T 17 cells, comprised of RORγt-expressing γδ T cells and T helper 17 cells in the skin-draining lymph nodes of these mice. Contradictory to previous suggestions, this expansion was not a result of a direct negative feedback loop because we found no expansion of T 17 cells in mice lacking IL-17 signaling specifically in T cells. Instead, we found that the T 17 expansion depended on the microbiota and was observed only when KCs were deficient for IL-17RA signaling. Indeed, mice that lack IL-17RA only in KCs showed an increased susceptibility to experimental epicutaneous infection with S. aureus together with an accumulation of IL-17A-producing γδ T cells. We conclude that deficiency of IL-17RA on KCs leads to microbiota dysbiosis in the skin, which triggers the expansion of IL-17A-producing T cells. Our data show that KCs are the primary target cells of IL-17A and IL-17F, coordinating the defense against microbial invaders in the skin., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune-responsiveness to SARS-CoV-2 mRNA vaccination is reduced in kidney transplant recipients (KTRs). Previous reports point to a role of mycophenolic acid (MPA). Our observational cohort study included all KTRs at University Hospital Zurich receiving two SARS-CoV-2 mRNA vaccine doses more than 6 months post-transplantation, who were assessed by measuring anti-spike immunoglobulin G (IgG). We applied principles of therapeutic drug monitoring (TDM) to correlate MPA exposure and lymphocyte counts with SARS-CoV-2 IgG. MPA trough levels differ largely among KTRs with a median of 3.1 mg/L (range 0.7-9.5 mg/L). 34 of 84 KTRs (40%) developed positive SARS-CoV-2 IgG after two vaccine doses. KTRs who developed positive SARS-CoV-2 IgG showed significantly higher eGFR ( p < 0.001), lower MPA trough levels ( p < 0.001) and higher CD19 + lymphocytes ( p < 0.001). MPA trough levels <2.5 mg/l and CD19 + lymphocytes >40/μl identify KTRs with seroconversion. Upon logistic regression, MPA trough levels <2.5 mg/L were associated with a 7-fold (CI 95%: 1.589-29.934) and ciclosporin use with a 6-fold (CI 95%: 1.148-30.853) increase in the odds of seroconversion. Our study indicates that immune-responsiveness to SARS-CoV-2 mRNA vaccines correlates with MPA exposure measured by MPA trough level but argues against a class effect of MPA. TDM-guided MPA dosing may be a strategy to increase seroconversion rate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 von Moos, Rho, Dammann, Kokkonen, Mueller and Schachtner.)

Aim: Noninvasive identification of haemodialysis patients at high risk of cardiovascular events and death might improve their outcome. Growth differentiation factor 15 is a prognostic biomarker in multiple disease entities, including cardiovascular disease. The aim of this study was to assess the association between plasma GDF-15 and mortality in a cohort of haemodialysis patients., Methods: Circulating GDF-15 was measured in 30 patients after a regular haemodialysis session, followed by a clinical follow-up for all-cause death. Measurements were performed using the Proseek Multiplex Cardiovascular disease panels (Olink Proteomics AB) and validated using the Elecsys GDF-15 electrochemiluminescence immunoassay on a Cobas E801 analyzer (Roche Diagnostics)., Results: During a median of 38 months, 9 patients (30%) died. Seven deaths occurred in the group of patients with a circulating GDF-15 above the median and two in the group with lower GDF-15. Mortality was significantly higher in patients with circulating GDF-15 levels above the median, log-rank P  = 0.044. The performance of circulating GDF-15 to predict long-term mortality has an area under the ROC curve of 0.76, P  = 0.028. Prevalence of most relevant comorbidities and the Charlson comorbidity index were similar across the two groups. A high agreement with a correlation among both diagnostic methods was observed (Spearman's rho = 0.83, P < 0.001)., Conclusion: Plasma GDF-15 displays promising prognostic properties for the prediction of long-term survival beyond clinical parameters in patients on maintenance haemodialysis., Competing Interests: AM reports research grants from Abbott Diagnostics, Roche, Sphyngotec, 4TEEN4, advisory boards for Adrenomed, Corteria, Fire1, Roche, honoraria from Merck, Novartis, material support from Sphyngotec, outside the current work. All authors declare that they have no conflicts of interest., (Copyright © 2023 Christelle Calen et al.)

Background: Despite substantial improvements in short-term kidney allograft survival, median long-term survival remains at a standstill. It is unclear whether and to what extent a transplant centre's post-transplant care influences long-term outcomes., Methods: We retrospectively analysed 501 single kidney transplant recipients (KTRs) who underwent transplantation between 2009 and 2018 and did not develop rejection or de novo donor-specific antibodies (dnDSA) within the first post-transplant year. After that, KTRs were either followed exclusively every 3 months by the transplant centre ( n  = 197) or every 3 months by local nephrologists ( n  = 304) with only yearly follow-up by the transplant centre. We analysed kidney allograft outcomes regarding estimated glomerular filtration rate (eGFR) decline, proteinuria, development of dnDSA and rejection., Results: No differences between the two groups were observed in the baseline characteristics and the characteristics at the end of the first post-transplant year ( P  > .05). KTRs followed by local nephrologists were comparable to KTRs followed by the transplant centre concerning patient survival ( P  = .541), kidney allograft survival ( P  = .385), eGFR decline ( P  = .488), progression of proteinuria ( P  > .05), the development of dnDSA ( P  = .335) and T-cell-mediated rejection ( P  = .480). KTRs followed by the transplant centre were more likely to undergo indication biopsies in case of allograft dysfunction and dnDSA ( P  < .001). Antibody-mediated rejection was diagnosed earlier and more frequently ( P  = .059), recurrent glomerulonephritis was diagnosed earlier and more frequently ( P  = .026) and immunosuppression was modified earlier and more frequently in response to histological findings ( P  = .038)., Conclusions: Our findings suggest that close collaboration between local nephrologists and the transplant centre ensures good allograft outcomes independent of the caregiver. Greater biopsy activity in the transplant centre allows for earlier diagnosis of allograft dysfunction as the basis for novel treatment options., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Indication biopsies for deterioration of kidney allograft function often require follow-up biopsies to assess treatment response or lack of improvement. Immune-mediated injury, namely borderline rejection (BLR), T-cell mediated rejection (TCMR), or antibody-mediated rejection (ABMR), results from preformed or de novo alloreactivity due to donor and recipient HLA-mismatches. The impact of HLA-mismatches on alloreactivity is determined by highly immunogenic HLA-epitopes., Methods: We analyzed 123 kidney transplant recipients (KTRs) from 2009 to 2019 who underwent a first indication and a follow-up biopsy. KTRs were divided into three groups according to the first biopsy: No rejection (NR)/BLR (n=68); TCMR (n=21); ABMR (n=34). The HLA-derived epitope-mismatches were calculated using the Predicted Indirectly Recognizable HLA-Epitopes (PIRCHE-II) algorithm., Results: Group NR/BLR: KTRs with higher total PIRCHE-II scores were more likely to develop TCMR in the follow-up biopsy (p=0.031). Interestingly, these differences were significant for both HLA-class I- (p=0.017) and HLA-class II-derived (p=0.017) PIRCHE-II scores. Group TCMR: KTRs with ongoing TCMR in the follow-up biopsy were more likely to show higher total PIRCHE-II scores (median 101.50 vs. 74.00). Group ABMR: KTRs with higher total PIRCHE-II scores were more likely to show an increase in the microvascular inflammation score in the follow-up biopsy. This difference was more pronounced for the HLA-class II-derived PIRCHE-II scores (median 70.00 vs. 31.76; p=0.086)., Conclusions: PIRCHE-II scores may prove useful as a biomarker to predict the histopathological changes of immune-related injury from a first indication to a follow-up biopsy. This immunological risk stratification may contribute to individualized treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spitznagel, Matter, Kaufmann, Nilsson, von Moos and Schachtner.)

Introduction: Accelerometry, the clinically valued standard of physical activity monitoring, has limited acceptance in transplantation rehabilitation; therefore, the International Physical Activity Questionnaire (IPAQ) self-report instrument is widely used. However, while the IPAQ's repeatability is good, its criterion validity is unsatisfactory. We hypothesized that adding a concise oral introduction would help overcome this shortfall., Materials and Methods: This is a secondary analysis of a RCT in a sample of kidney transplant recipients that underwent observational follow-up. We assessed criterion validity of our modified version of the four-item IPAQ-Short Form (mIPAQ-SF) via Pearson, and test-retest reliability via intraclass correlation coefficients. The main difference in the new version is an oral pre-measurement introduction to the questionnaire's concepts. We compared our results with those of published studies., Results: Post-kidney-transplantation data of 92 patients were analyzed. Across the four IPAQ-SF/mIPAQ-SF items, values of correlations between mIPAQ-SF responses and accelerometry records ranged from 0.07 (min in vigorous activity) to 0.35 (min in moderate activity) for criterion validity, and from 0.19 (days with moderate activity) to 0.58 (min in moderate activity) for test-retest reliability., Discussion: Regarding moderate-to-vigorous physical activity, mIPAQ-SF self-reports' correlations to accelerometry records improved considerably on those of the IPAQ-SF (r = 0.18 vs. r = 0.33), i.e., improved criterion validity. We therefore conclude that a pre-measurement oral explanation of key IPAQ-SF/mIPAQ concepts enhances criterion validity regarding self-reported moderate-to-vigorous physical activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kohlbrenner, von Moos and Schmid-Mohler.)

Background: Cancer risk is increased by 2- to 4-fold in kidney transplant recipients (KTRs) compared with the general population. Little attention, however, has been given to KTRs with ultra long-term survival >20 years., Methods: We studied 293 of 1241 KTRs (23.6%), transplanted between 1981 and 1999, who showed kidney allograft survival >20 years. These long-term survivors were analysed for cancer development, cancer type, cancer-associated risk factors and patient and allograft outcomes., Results: By 10, 20 and 30 years post-transplantation, these long-term KTRs showed a cancer rate of 4.4%, 14.6% and 33.2%, and a non-melanoma skin cancer (NMSC) rate of 10.3%, 33.5% and 76.8%, respectively. By recipients' ages of 40, 60 and 80 years, KTRs showed a cancer rate of 3.4%, 14.5% 55.2%, and a NMSC rate of 1.7%, 31.6% and 85.2%, respectively. By 30 years post-transplantation, post-transplant lymphoproliferative disorder (PTLD) showed the highest incidence of 8.5%, followed by renal cell carcinoma (RCC) with 5.1%. Risk factors associated with the development of cancer were only recipient age (P = 0.016). Smoking history was associated with the risk of lung cancer (P = 0.018). Risk factors related to the development of NMSC included recipient age (P = 0.001) and thiazide diuretics (P = 0.001). Cancer increased the risk of death by 2.4-fold (P = 0.002), and PTLD increased the risk of kidney allograft loss by 6.5-fold (P = 0.001). No differences were observed concerning the development of donor-specific antibodies (P > 0.05)., Conclusions: In long-term KTRs, cancer is a leading cause of death. PTLD remains the most common cancer type followed by RCC. These results emphasize the need for focused long-term cancer surveillance protocols., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background and Objectives: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small., Design, Setting, Participants, & Measurements: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America., Results: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence., Conclusions: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss., (Copyright © 2021 by the American Society of Nephrology.)

Patients with severe facial deformities present serious dysfunctionalities along with an unsatisfactory aesthetic facial appearance. Several methods have been proposed to specifically plan the interventions on the patient's needs, but none of these seem to achieve a sufficient level of accuracy in predicting the resulting facial appearance. In this context, a deep knowledge of what occurs in the face after bony movements in specific surgeries would give the possibility to develop more reliable systems. This study aims to propose a novel 3D approach for the evaluation of soft tissue zygomatic modifications after zygomatic osteotomy; geometrical descriptors usually involved in face analysis tasks, i.e., face recognition and facial expression recognition, are here applied to soft tissue malar region to detect changes in surface shape. As ground truth for zygomatic changes, a zygomatic openness angular measure is adopted. The results show a high sensibility of geometrical descriptors in detecting shape modification of the facial surface, outperforming the results obtained from the angular evaluation.

Background: Improved understanding and assessment of the complex physiology of volume regulation in haemodialysis (HD) patients are required to improve patient care and reduce mortality associated with fluid overload (FO)., Methods: We searched for FO-related biomarkers among 184 peptides associated with cardiovascular disease in a cohort of 30 HD patients. First, we assessed the direct impact of HD on the peptides of interest by comparing plasma concentrations before and after treatment. Then, we compared cardiovascular peptide profiles between patients with and without FO as defined by bioimpedance analysis (BIA). The plasma concentration of selected candidate biomarkers for FO was determined by enzyme-linked immunosorbent assay (ELISA) and correlated with previously described FO-related clinical and laboratory parameters. For validation, results were confirmed in an independent cohort of 144 HD patients., Results: We found seven peptides positively [NT-proBNP, B-type natriuretic peptide (BNP), vascular endothelial growth factor D (VEGFD), tumour necrosis factor-related apoptosis-inducing ligand receptor 2, growth differentiation factor 15, tumour necrosis factor ligand superfamily member 13B, chitinase-3-like protein 1] and five negatively (leptin, renin, epidermal growth factor receptor, interleukin-1 receptor antagonist, myeloblastin) correlated to FO. In addition to natriuretic peptides, VEGFD emerged as third peptide highly correlated with BIA (ρ = 0.619, P < 0.0001). In line with this, VEGFD concentration verified by ELISA correlated with BIA, BNP and soluble CD146 but not with vascular endothelial growth factor C (VEGFC). Notably, levels of VEGFD were unrelated to cardiac systolic function (P = 0.63), contrary to BNP (P = 0.0003). Finally, we observed that 1-year all-cause mortality was higher in patients with high BNP (P = 0.0002), FO (defined by BIA, P = 0.04) and high VEGFD (P = 0.02), but not with high VEGFC (P = 0.48)., Conclusion: VEGFD is a novel FO-related biomarker with unique diagnostic and prognostic properties., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Donor organ shortage, growing waiting lists and substantial organ discard rates are key problems in transplantation. The critical importance of organ quality in determining long-term function is becoming increasingly clear. However, organ quality is difficult to predict. The lack of good measures of organ quality is a serious challenge in terms of acceptance and allocation of an organ. The underlying review summarizes currently available methods used to assess donor organ quality such as histopathology, clinical scores and machine perfusion characteristics with special focus on molecular analyses of kidney quality. The majority of studies testing molecular markers of organ quality focused on identifying organs at risk for delayed graft function, yet without prediction of long-term graft outcome. Recently, interest has emerged in looking for molecular markers associated with biological age to predict organ quality. However, molecular gene sets have not entered the clinical routine or impacted discard rates so far. The current review critically discusses the potential reasons why clinically applicable molecular quality assessment using early kidney biopsies might not have been achieved yet. Besides a critical analysis of the inherent limitations of surrogate markers used for organ quality, i.e., delayed graft function, the intrinsic methodological limitations of studies assessing organ quality will be discussed. These comprise the multitude of unpredictable hits as well as lack of markers of nephron mass, functional reserve and regenerative capacity., (Copyright © 2020 von Moos, Akalin, Mas and Mueller.)

IL-17-producing CD8 + (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8 + T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.

Background: Older age at organ transplantation is associated with increased risk of infection and malignancy but reduced risk of cellular rejection. De novo donor-specific anti-HLA antibodies ( dn DSA), are key biomarkers associated with reduced long-term allograft survival, yet there is a lack of data focusing on age-associated changes., Methods: Development of dn DSA was restrospectively analyzed in all subjects who received a kidney transplant at the University Hospital Zurich between 01/2006 and 02/2015. Follow up continued until 03/2016. The incidence of dn DSA in different age categories was compared with special focus on the extremes of age: children < 10 years ( n  = 19) and adults ≥60 years of age ( n  = 110)., Results: Incidence of dn DSA gradually decreased with age, with older recipients having a significantly lower risk (HR 0.21, p  = 0.0224) compared to pediatric recipients. Cumulative incidence of dn DSA at 2, 5 and 10 years was 6.2, 9.1 and 36% in the older recipients versus 5.3, 29.5 and 47.1% in pediatric recipients. Median time to development of dn DSA was similar (older 720 days, min 356, max 3646 days; children 1086 days, min 42, max 2474 days). Annual incidence was highest within the first two years after transplantation in the older recipients and peaked in years two to four in pediatric recipients. Dn DSA were predominantly class II. More dn DSA were observed with cyclosporine as compared to tacrolimus., Conclusion: Older kidney transplant recipients have a lower risk of developing dn DSA than pediatric recipients, pointing towards reduced humoral immune reactivity with increasing age. This observation raises the question of adjustment in immunosuppression., Competing Interests: The study was approved by the local ethics committee of Zurich (protocol number: KEK-ZH-Nr. 2017–00500).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The pathology of psoriasis strongly depends on IL-17A. Monoclonal antibodies blocking either the cytokine or its receptor are among the most efficient treatments for psoriatic patients. Keratinocytes can be activated upon exposure to IL-17A and tumor necrosis factor-α and secrete secondary cytokines and chemokines in the inflamed skin. In psoriasis and its imiquimod-induced mouse model, a strong skin infiltration of neutrophils and inflammatory monocytes can be observed. However, to date, it is not clear how exactly those cellular populations are attracted to the skin and how they contribute to the pathogenesis of the disease. To define the crucial cell type responding to IL-17 and initiating the downstream pathology in psoriasis-like dermatitis, we used mice specifically lacking the IL-17 receptor (IL-17RA) in different cell types. Deletion of IL-17RA in T cells or myeloid had no impact on disease development. Only deletion of this receptor in keratinocytes reflected the full-body deletion of IL-17RA, resulting in strongly reduced dermatitis development. Imiquimod treatment of those IL-17 signaling-deficient mice maintained high monocytic infiltration but failed to attract neutrophils into the skin. We conclude that keratinocytes are a critical cellular target for IL-17A-mediated neutrophil attraction and psoriasis development., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Accurate volume status evaluation and differentiation of cardiac and non-cardiac components of overhydration (OH) are fundaments of optimal haemodialysis (HD) management., Methods: This study, by combining bioimpedance measurements, cardiovascular biomarkers and echocardiography, aimed at dissecting OH into its major functional components, and prospectively tested the association between cardiac and non-cardiac components of OH with mortality. In the first part, we validated soluble CD146 (sCD146) as a non-cardiac biomarker of systemic congestion in a cohort of 30 HD patients. In the second part, we performed a prospective 1-year follow-up study in an independent cohort of 144 HD patients., Results: sCD146 incrementally increased after the short and long intervals after HD (+53 ng/mL, P = 0.006 and  +91 ng/mL, P < 0.001), correlated with OH as determined by bioimpedance and well-diagnosed OH (area under the receiver operating characteristics curve 0.72, P = 0.005). The prevalence of OH was lower for low-sCD146 and low-BNP patients (B-type natriuretic peptide, 29%) compared with subjects with either one or both biomarkers elevated (65-74%, P < 0.001). Notably, most low-BNP but high-sCD146 subjects were overhydrated. Systolic dysfunction was 2- to 3-fold more prevalent among high-BNP compared with low-BNP patients (44-68% versus 21-23%, chi-square P < 0.001), regardless of sCD146. One-year all-cause mortality was markedly higher in patients with high-BNP (P = 0.001) but not with high-sCD146. In multivariate analysis, systolic dysfunction and BNP, but not OH, were associated with lower survival., Conclusions: The combination of BNP and sCD146 dissects OH into functional components of prognostic value. OH in HD patients is associated with higher mortality only if resulting from cardiac dysfunction.