The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress.

An elevated frequency of DNA replication defects is associated with diabetes and cancer. However, data linking these nuclear perturbations to the onset or progression of organ complications remained unexplored. Here, we report that RAGE (Receptor for Advanced Glycated Endproducts), previously believed to be an extracellular receptor, upon metabolic stress localizes to the damaged forks. There it interacts and stabilizes the minichromosome-maintenance (Mcm2-7) complex. Accordingly, RAGE deficiency leads to slowed fork progression, premature fork collapse, hypersensitivity to replication stress agents and reduction of viability, which was reversed by the reconstitution of RAGE. This was marked by the 53BP1/OPT-domain expression and the presence of micronuclei, premature loss-of-ciliated zones, increased incidences of tubular-karyomegaly, and finally, interstitial fibrosis. More importantly, the RAGE-Mcm2 axis was selectively compromised in cells expressing micronuclei in human biopsies and mouse models of diabetic nephropathy and cancer. Thus, the functional RAGE-Mcm2/7 axis is critical in handling replication stress in vitro and human disease.

Verification of sex- and age-specific reference intervals for 13 serum steroids determined by mass spectrometry: evaluation of an indirect statistical approach.

OBJECTIVES: Conventionally, reference intervals are established by direct methods, which require a well-characterized, obviously healthy study population. This elaborate approach is time consuming, costly and has rarely been applied to steroid hormones measured by mass spectrometry. In this feasibility study, we investigate whether indirect methods based on routine laboratory results can be used to verify reference intervals from external sources. METHODS: A total of 11,259 serum samples were used to quantify 13 steroid hormones by mass spectrometry. For indirect estimation of reference intervals, we applied a "modified Hoffmann approach", and verified the results with a more sophisticated statistical method (refineR). We compared our results with those of four recent studies using direct approaches. RESULTS: We evaluated a total of 81 sex- and age-specific reference intervals, for which at least 120 measurements were available. The overall agreement between indirectly and directly determined reference intervals was surprisingly good as nearly every fourth reference limit could be confirmed by narrow tolerance limits. Furthermore, lower reference limits could be provided for some low concentrated hormones by the indirect method. In cases of substantial deviations, our results matched the underlying data better than reference intervals from external studies. CONCLUSIONS: Our study shows for the first time that indirect methods are a valuable tool to verify existing reference intervals for steroid hormones. A simple "modified Hoffmann approach" based on the general assumption of a normal or lognormal distribution model is sufficient for screening purposes, while the refineR algorithm may be used for a more detailed analysis.

The value of intraoperative MRI for resection of functional pituitary adenomas-a critical assessment of a consecutive single-center series of 114 cases.

This series sought to evaluate the role of intraoperative MRI (iMRI) for resection of functional pituitary adenomas (FPAs). We retrospectively reviewed clinical data of 114 consecutive FPAs with excessive hormone secretion treated with transsphenoidal surgery and iMRI during 01/2010-12/2017. We focused on iMRI findings, extend of resection and postoperative hormonal remission. Variables of incomplete resections and persistent hormone excess were evaluated by binary regression. Patients with FPAs presented with hypercortisolism (n = 23, 20%), acromegaly (n = 56, 49%), and as prolactinomas (n = 35, 31%) resistant to medical treatment. Preoperative MRI showed 81 macroadenomas (71%) and optic system involvement in 41 cases (36%). IMRI was suggestive for residual tumor in 51 cases (45%). Re-inspection of the cavity cleared equivocal findings in 16 cases (14%). Additional tumor was removed in 22 cases (19%). Complete resection was achieved in 95 cases (83%). Postoperative morbidity was low (1.7% revision surgeries, 0.8% permanent diabetes insipidus). Overall hormonal remission-rate was 59% (hypercortisolism 78%, acromegaly 52%, prolactinoma 57%). Supra- and parasellar invasion and preoperative visual impairment were significant predictors for incomplete resections despite use of iMRI. Risk for persistent hormone excess was increased sevenfold after incomplete resections. IMRI enabled reliable identification of tumor remnants during surgery and triggered further resection in a considerable proportion of cases. Nevertheless, tumor size and invasiveness set persistent boundaries to the completeness of resections. The low rate of surgical complications could point at a less invasive iMRI-guided surgical approach while achieving a complete tumor resection was a crucial determinant for hormonal outcome.

Interpretation of myocardial injury subtypes in COVID-19 disease per fourth version of Universal Definition of Myocardial Infarction.

BACKGROUND: Application of the 4th version of Universal Definition of Myocardial Infarction (UDMI) to characterize rates and prognostic relevance of myocardial injury in COVID-19 disease. METHODS: This retrospective, single-centre observational study enrolled 104 patients hospitalized with SARS-CoV-2 infection. Kaplan-Meier analysis and multivariate Cox regression were used to identify influence of acute or chronic myocardial injury on a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation) and secondary endpoint (mortality, incident acute myocardial injury during hospitalization, incident venous thrombosis, pulmonary embolism or stroke). RESULTS: A total of 27 (26.0%) patients presented with chronic myocardial injury, and 19 (18.3%) with acute myocardial injury. 42 patients(40.4%) developed an incident myocardial injury during hospitalization. The presence of acute or chronic myocardial injury on admission and incident myocardial injury during hospitalization were associated with higher rates of endpoints. Independent predictors for the primary endpoint were higher severity stages according to Siddiqi et al. classification system and history of dyslipidaemia. Maximal hs-cTnT and D-dimer concentrations during hospitalization showed an association (r = 0.61). CONCLUSIONS: Objective description of myocardial injury according to the 4th UDMI in the current COVID-19 pandemic is crucial in order to discriminate patients with acute myocardial infarction and acute, chronic or incident myocardial injury.

Improvement of renal function after transcatheter aortic valve replacement and its impact on survival.

BACKGROUND: Chronic kidney disease as well as acute kidney injury are associated with adverse outcomes after transcatheter aortic valve replacement (TAVR). However, little is known about the prognostic implications of an improvement in renal function after TAVR. METHODS: Renal improvement (RI) was defined as a decrease in postprocedural creatinine in µmol/l of ≥1% compared to its preprocedural baseline value. A propensity score representing the likelihood of RI was calculated to define patient groups which were comparable regarding potential confounders (age, sex, BMI, NYHA classification, STS score, log. EuroSCORE, history of atrial fibrillation/atrial flutter, pulmonary disease, previous stroke, CRP, creatinine, hsTNT and NT-proBNP). The cohort was stratified into 5 quintiles according to this propensity score and the survival time after TAVR was compared within each subgroup. RESULTS: Patients in quintile 5 (n = 93) had the highest likelihood for RI. They were characterized by higher creatinine, lower eGFR, higher NYHA class, higher NT-proBNP, being mostly female and having shorter overall survival time. Within quintile 5, patients without RI had significantly shorter survival compared to patients with RI (p = 0.002, HR = 0.32, 95% CI = [0.15-0.69]). There was no survival time difference between patients with and without RI in the whole cohort (p = 0.12) and in quintiles 1 to 4 (all p > 0.16). Analyses of specific subgroups showed that among patients with NYHA class IV, those with RI also had a significant survival time benefit (p < 0.001, HR = 0.15; 95%-CI = [0.05-0.44]) compared to patients without RI. CONCLUSIONS: We here describe a propensity score-derived specific subgroup of patients in which RI after TAVR correlated with a significant survival benefit.

Benefits of peritoneal ultrafiltration in HFpEF and HFrEF patients.

BACKGROUND: Peritoneal ultrafiltration (pUF) in refractory heart failure (HF) reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality. Nevertheless, there are insufficient data about which patient cohort benefits the most. The objective of this study was to compare pUF in HFrEF and HFpEF, focusing on functional status, hospitalizations, surrogate endpoints and mortality. METHODS: This study involves 143 patients, who could be classified as either HFpEF (n = 37, 25.9%) or HFrEF (n = 106, 74.1%) and who received pUF due to refractory HF. RESULTS: Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dl) and HFpEF (27.8 ± 13.2 mg/dl). Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, P <  0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, P <  0.001). CRP decreased in HFrEF (19.4 ± 17.6 mg/l to 13.7 ± 21.4 mg/l, P = 0.018) and HFpEF (33.7 ± 52.6 mg/l to 17.1 ± 26.3 mg/l, P = 0.004). Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, P = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, P = 0.005). LVEF improved only in HFrEF (25.9 ± 6.82% to 30.4 ± 12.2%, P = 0.046). BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 P > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, P = 0.006). Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, P <  0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, P = 0.005). CONCLUSIONS: pUF offers various benefits in HFpEF and HFrEF, but there are also substantial differences. In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage. However, LVEF was only found to be improved in HFrEF patients. While pUF can now be regarded as an option to supplement classical HF therapy, further studies are desirable to obtain specifications about pUF in HFpEF, HFmEF and HFrEF patients.

Cell cycle arrest and cell death correlate with the extent of ischaemia and reperfusion injury in patients following kidney transplantation - results of an observational pilot study.

A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7 days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10 days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors.

Hypercalcemia, necrotizing pancreatitis and bone lesions: a benign cause.

Primary Hyperparathyroidism is asymptomatic in most patients (PHPT). We report a case of PHPT in a young male patient. He presented with severe pancreatitis due to hypercalcemia and multiple bone lesions resulting in pathological fractures. The patients recovered rapidly after parathyroidectomy.

Increased peritoneal damage in glyoxalase 1 knock-down mice treated with peritoneal dialysis.

BACKGROUND: Peritoneal dialysis (PD) is limited by peritoneal fibrosis and ultrafiltration failure. This is in part caused by the high concentration of glucose degradation products (GDPs) present in PD fluids (PDF) as a consequence of heat sterilization. Existing research in long-term PD has mainly dealt with the toxicity induced by GDPs and the development of therapeutic strategies to reduce the cellular burden of GDPs. Currently, there are few data regarding the potential role of detoxification systems of GDP in PD. In this study, the role of glyoxalase 1 (Glo1), the major detoxification pathway for dicarbonyl-derived GD such as methylglyoxal (MG) and glyoxal (Gx), was investigated in vivo using heterozygous knock-down mice for Glo1 (Glo1(-/+)). METHODS: Wild-type (WT) and Glo1(-/+) mice were repeatedly treated with PDF containing low and high amounts of GDP, particularly with respect to the content of dicarbonyls. After 12 weeks of treatment with PDF, peritoneal damage and function were evaluated. RESULTS: Glo1(-/+) mice treated with PDF showed increased formation of advanced glycation endproduct (AGE) when compared with WT mice, particularly the Gx-derived AGE, carboxymethyl-lysine. This was associated with increased inflammation, neovascularization, increased peritoneal fibrosis and impaired peritoneal function. CONCLUSIONS: This study suggests a pivotal and underestimated role for Glo1 as a detoxifying enzyme in GDP-associated peritoneal toxicity in PD. The indirect and direct modulation of Glo1 may therefore offer a new therapeutic option in prevention of GDP-induced peritoneal damage in PD.

Human RAGE antibody protects against AGE-mediated podocyte dysfunction.

BACKGROUND: Residual renal function (RRF) contributes to better patient survival in peritoneal dialysis (PD). It is known that glucose degradation products (GDP) and advanced glycation end-products (AGE) resorbed from the peritoneal cavity do not only cause local peritoneal toxicity but also systemic damage resulting in a loss of RRF. We hypothesize that GDP and AGE affect the structure and function of podocytes and investigate whether these effects can be rescued by human RAGE antibody (hRAGEab) to prevent AGE/RAGE interaction and podocyte damage. METHODS: Differentiated human podocytes were pre-incubated with ±hRAGEab to block the AGE/RAGE interaction and incubated afterwards either with control solution (control), PD fluid (PDF) or a GDP mixture (GDP) for 48 h. We analysed podocyte damage and rescue by hRAGEab using immunofluorescence, western blot, enzyme-linked immunosorbent assay and a functional migration assay. For quantitation, a semiquantitative score was used. RESULTS: When pre-incubating podocytes with hRAGEab, damage mediated by PDF and GDP was reduced. We observed lower expression of AGE in PDF and GDP as well as decreased levels of inflammation as shown by activation of nuclear factor kappa B and interleukin-6 release. The reorganization of the podocyte actin cytoskeleton was reduced in the presence of hRAGEab as well as ameliorated synaptopodin expression could be observed, both functionally associated with normal podocyte motility. Finally, podocytes underwent less apoptosis. CONCLUSIONS: It has been investigated that GDP-containing PDF causes a loss of RRF in PD. Our findings suggest that hRAGEab confers protection against PDF- and GDP-induced podocyte dysfunction. Blocking the AGE/RAGE interaction provides specific protective effects against PDF- and GDP-induced cytoskeletal reorganization, dynamics and stabilizes podocyte survival; this might be an implication for the preservation of RRF in PD.

Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury - a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts.

INTRODUCTION: Acute kidney injury (AKI) is associated with a high mortality of up to 60%. The mode of renal replacement therapy (intermittent versus continuous) has no impact on patient survival. Sustained low efficiency dialysis using a single-pass batch dialysis system (SLED-BD) has recently been introduced for the treatment of dialysis-dependent AKI. To date, however, only limited evidence is available in the comparison of SLED-BD versus continuous veno-venous hemofiltration (CVVH) in intensive care unit (ICU) patients with AKI. METHODS: Prospective, randomized, interventional, clinical study at a surgical intensive care unit of a university hospital. Between 1 April 2006 and 31 January 2009, 232 AKI patients who underwent renal replacement therapy (RRT) were randomized in the study. Follow-up was assessed until 30 August 2009. Patients were either assigned to 12-h SLED-BD or to 24-h predilutional CVVH. Both therapies were performed at a blood flow of 100 to 120 ml/min. RESULTS: 115 patients were treated with SLED-BD (total number of treatments n = 817) and 117 patients with CVVH (total number of treatments n = 877).The primary outcome measure, 90-day mortality, was similar between groups (SLED: 49.6% vs. CVVH: 55.6%, P = 0.43). Hemodynamic stability did not differ between SLED-BD and CVVH, whereas patients in the SLED-BD group had significantly fewer days of mechanical ventilation (17.7 ± 19.4 vs. 20.9 ± 19.8, P = 0.047) and fewer days in the ICU (19.6 ± 20.1 vs. 23.7 ± 21.9, P = 0.04). Patients treated with SLED needed fewer blood transfusions (1,375 ± 2,573 ml vs. 1,976 ± 3,316 ml, P = 0.02) and had a substantial reduction in nursing time spent for renal replacement therapy (P < 0.001) resulting in lower costs. CONCLUSIONS: SLED-BD was associated with reduced nursing time and lower costs compared to CVVH at similar outcomes. In the light of limited health care resources, SLED-BD offers an attractive alternative for the treatment of AKI in ICU patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00322530.

Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis.

Residual renal function and the integrity of the peritoneal membrane contribute to morbidity and mortality among patients treated with peritoneal dialysis. Glucose and its degradation products likely contribute to the deterioration of the remnant kidney and damage to the peritoneum. Benfotiamine decreases glucose-induced tissue damage, suggesting the potential for benefit in peritoneal dialysis. Here, in a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peritoneal fibrosis, markers of inflammation, and neovascularization, resulting in improved characteristics of peritoneal transport. Furthermore, rats treated with benfotiamine exhibited lower expression of advanced glycation endproducts and their receptor in the peritoneum and the kidney, reduced glomerular and tubulointerstitial damage, and less albuminuria. Increased activity of transketolase in tissue and blood contributed to the protective effects of benfotiamine. In primary human peritoneal mesothelial cells, the addition of benfotiamine led to enhanced transketolase activity and decreased expression of advanced glycation endproducts and their receptor. Taken together, these data suggest that benfotiamine protects the peritoneal membrane and remnant kidney in a rat model of peritoneal dialysis and uremia.

Pre-transplant Type 2 Diabetes Mellitus Is Associated With Higher Graft Failure and Increased 5-Year Mortality After Heart Transplantation.

Aims: Cardiac transplant recipients often suffer from type 2 diabetes mellitus (T2DM) but its influence on graft failure and post-transplant mortality remains unknown. The aim of this study was to investigate the long-term effects of pre-transplant T2DM in patients after heart transplantation (HTX). Methods: This study included a total of 376 adult patients who received HTX at Heidelberg Heart Center between 01/01/2000 and 01/10/2016. HTX recipients were stratified by diagnosis of T2DM at the time of HTX. Patients with T2DM were further subdivided by hemoglobin A1c (HbA1c ≥ 7.0%). Analysis included donor and recipient data, immunosuppressive drugs, concomitant medications, post-transplant mortality, and causes of death. Five-year post-transplant mortality was further assessed by multivariate analysis (Cox regression) and Kaplan-Meier estimator. Results: About one-third of all HTX recipients had T2DM (121 of 376 [32.2%]). Patients with T2DM showed an increased 5-year post-transplant mortality (41.3% versus 29.8%; P = 0.027) and had a higher percentage of death due to graft failure (14.9% versus 7.8%; P = 0.035). Multivariate analysis showed T2DM (HR: 1.563; 95% CI: 1.053-2.319; P = 0.027) as an independent risk factor for 5-year mortality after HTX. Kaplan-Meier analysis showed a significantly better 5-year post-transplant survival of patients with T2DM and a HbA1c < 7.0% than patients with T2DM and a HbA1c ≥ 7.0% (68.7% versus 46.3%; P = 0.008) emphasizing the clinical relevance of a well-controlled T2DM in HTX recipients. Conclusion: Pre-transplant T2DM is associated with higher graft failure and increased 5-year mortality after HTX.

Emerging drugs for the treatment of transplant rejection.

INTRODUCTION: Kidney allograft rejection is an important cause of early and late allograft failure. The importance of antibody-mediated rejection especially in the context of late allograft failure has only recently been acknowledged. AREAS COVERED: This review summarizes new developments in the treatment of cellular and antibody-mediated kidney allograft rejection. Drugs presented here include monoclonal antibodies and novel innovative approaches such as proteasome and complement inhibition. In addition, other options for the treatment of allograft rejection such as the administration of intravenous immune globulins or the use of plasmapheresis and immunoadsorption are discussed. EXPERT OPINION: Especially the treatment of chronic antibody-mediated rejection represents a challenge and new therapeutic options are needed.

EASIX for Prediction of Outcome in Hospitalized SARS-CoV-2 Infected Patients.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has evoked a pandemic that challenges public health-care systems worldwide. Endothelial cell dysfunction plays a key role in pathophysiology, and simple prognosticators may help to optimize allocation of limited resources. Endothelial activation and stress index (EASIX) is a validated predictor of endothelial complications and outcome after allogeneic stem cell transplantation. Aim of this study was to test if EASIX could predict life-threatening complications in patients with COVID-19. METHODS: SARS-CoV-2-positive, hospitalized patients were enrolled onto a prospective non-interventional register study (n=100). Biomarkers were assessed at hospital admission. Primary endpoint was severe course of disease (mechanical ventilation and/or death, V/D). Results were validated in 126 patients treated in two independent institutions. RESULTS: EASIX at admission was a strong predictor of severe course of the disease (odds ratio for a two-fold change 3.4, 95%CI 1.8-6.3, p<0.001), time to V/D (hazard ratio (HR) for a two-fold change 2.0, 95%CI 1.5-2.6, p<0.001) as well as survival (HR for a two-fold change 1.7, 95%CI 1.2-2.5, p=0.006). The effect was retained in multivariable analysis adjusting for age, gender, and comorbidities and could be validated in the independent cohort. At hospital admission EASIX correlated with increased suppressor of tumorigenicity-2, soluble thrombomodulin, angiopoietin-2, CXCL8, CXCL9 and interleukin-18, but not interferon-alpha. CONCLUSION: EASIX is a validated predictor of COVID19 outcome and an easy-to-access tool to segregate patients in need for intensive surveillance.

Validation of two severity scores as predictors for outcome in Coronavirus Disease 2019 (COVID-19).

BACKGROUND: An established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier-a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications. METHODS: In this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades. RESULTS: Of 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, p<0.001 and aHR 2.08, p<0.001), for the secondary endpoint (aHR 2.12, p<0.001 and aHR 1.79, p<0.001) and mortality (aHR 2.30, p = 0.071 and aHR 1.98, p = 0.017). Both classification systems showed very good agreement regarding initial grading and good agreement regarding progression of severity stages. CONCLUSIONS: Standardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.

Appropriateness of CT pulmonary angiograms according to current diagnostic guidelines based on risk stratification: A retrospective single-center study.

BACKGROUND AND AIM: Assessment of appropriateness of CT pulmonary angiograms (CTPA) in patients with suspected pulmonary embolism (PE) is based on risk stratification algorithms such as simplified the Geneva Score (sGS) in combination with D-dimer blood tests. The aim of this study was to validate the diagnostic yield and appropriateness of CTPA examinations in accordance with 2014 European Society of Cardiology (ESC) guidelines. MATERIALS AND METHODS: Data from 155 outpatients who underwent CTPA for clinical suspicion of PE were gathered from the radiology information system (RIS) and the clinical information system (CIS). We assessed the presence of sGS items and D-dimer blood test results in RIS from CTPA request forms and from clinical documentation in CIS. RESULTS: Based on the RIS, there were 2.6% patients with high (sGS≥3) and 97.4% patients with low pre-test PE probability (sGS<3), and CTPA indication was formally comprehendible in 75.5% using sGS and D-dimer blood tests. Based on RIS and CIS data in combination, there were 41.3% patients with high and 58.7% patients with low pre-test PE probability, and CTPA indication was formally comprehendible in 88.4%. Using RIS and CIS in combination, PE probability was upgraded from low to high probability in 39.7% compared with RIS alone. In 12.9%, there was a lack of data in RIS for CTPA justification. CONCLUSION: There is a high diagnostic yield when applying current diagnostic guidelines to our data. There was however a notable discrepancy between the data transferred to the CTPA request forms from the full clinical documentation, therefore not readily available for clinical decision making.

Elevated Expression of the RAGE Variant-V in SCLC Mitigates the Effect of Chemotherapeutic Drugs.

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy with a very high mortality rate. A prominent part of this is because these carcinomas are refractory to chemotherapies, such as etoposide or cisplatin, making effective treatment almost impossible. Here, we report that elevated expression of the RAGE variant-V in SCLC promotes homology-directed DNA DSBs repair when challenged with anti-cancer drugs. This variant exclusively localizes to the nucleus, interacts with members of the double-strand break (DSB) repair machinery and thus promotes the recruitment of DSBs repair factors at the site of damage. Increased expression of this variant thus, promotes timely DNA repair. Congruently, the tumor cells expressing high levels of variant-V can tolerate chemotherapeutic drug treatment better than the RAGE depleted cells. Our findings reveal a yet undisclosed role of the RAGE variant-V in the homology-directed DNA repair. This variant thus can be a potential target to be considered for future therapeutic approaches in advanced SSLC.

Uremia aggravates left ventricular remodeling after myocardial infarction.

BACKGROUND: Renal failure is a well-established cardiovascular risk factor. We hypothesized that uremia negatively affects post-myocardial infarction (MI) remodeling and left ventricular (LV) function and examined the pathohistological correlations. METHODS: Subtotally nephrectomized rats (SNX) and controls with MI only (MIC) were examined 1, 4 and 8 weeks after MI. MI size, ejection fraction (EF), cardiac fibrosis, vascular density and cardiomyocyte density were studied. RESULTS: The extension of MI was 0.08 +/- 0.02 in SNX versus 0.06 +/- 0.02 in MIC rats (p < 0.031). Prior to MI, EF was comparable in SNX and MIC (74 +/- 3 vs. 72 +/- 2%, n.s.). Despite a relatively small infarct size EF in SNX decreased to 58 +/- 4% 1 week after infarction and progressively worsened to 51 +/- 4% after 8 weeks. In MIC animals EF only slightly decreased 1 week after MI (70 +/- 3%) and remained unchanged at follow-up. In SNX animals LV end-diastolic diameter continuously increased following MI throughout the study period indicating accelerated remodeling. Furthermore, accelerated myocardial fibrosis was already notable 1 week after MI in SNX animals and the volume density of capillaries and cardiomyocytes was significantly lower in SNX rats. CONCLUSION: MI in experimental uremia is associated with progressive impairment of LV function, LV dilatation and accelerated myocardial fibrosis.

Analysis of Symptoms of COVID-19 Positive Patients and Potential Effects on Initial Assessment.

BACKGROUND: SARS-CoV-2 is a highly contagious virus, significantly impacting Germany among other countries since its emergence. Because of heterogeneous symptoms and a subset of patients even being asymptomatic at presentation, fast identification of infected patients remains challenging. OBJECTIVE: The goal of this study is the evaluation of different patient groups with a focus on symptoms and pre-existing illness at admission, as this is important for initial assessment and adequate emergency care. METHODS: COVID-19 positive patients at the University Hospital Heidelberg were retrospectively analyzed for disease history and symptoms at the initial presentation as well as mortality. The authors obtained institutional review board (IRB) approval by the Ethics Committee (Medical Faculty of Heidelberg University) prior to commencing the study. RESULTS: Dyspnea was more common in patients admitted to intermediate care/intensive care units (48 vs 13%, P<0.001) and showed a significantly higher percentage in the deceased (91 vs 48%, P=0.004). The symptoms of all presenting patients were highly variable, and many manifestations commonly associated with COVID-19 like cough, fever, and sore throat were only detected in a subset of patients, 60%, 43%, and 33%, respectively. CONCLUSION: Dyspnea was present significantly more often in patients dying of COVID-19 compared to all patients admitted to the IMC/ICU, necessitating adequate observation and monitoring. In all presenting patients, initial symptoms showed large variation; therefore, COVID should be considered as a main differential diagnosis at every patient presentation, and patients with high pre-test probability should, if possible, be isolated until testing results are known.