Cardiac fibrosis as a predictor for sudden cardiac death after transcatheter aortic valve implantation.

BACKGROUND: Cardiac fibrosis plays a major pathophysiological role in any form of chronic heart disease, and high levels are associated with poor outcome. Diffuse and focal cardiac fibrosis are different subtypes, which have different pathomechanisms and prognostic implications. The total fibrosis burden in endomyocardial biopsy tissue was recently proved to play an independent prognostic role in aortic stenosis patients after transcatheter aortic valve implantation (TAVI). AIMS: Here, for the first time, we aim to assess the specific impact of different fibrosis subtypes on sudden cardiac death (SCD) as a primary reason for cardiovascular mortality after TAVI. METHODS: The fibrosis pattern was assessed histologically in the left ventricular biopsies obtained during TAVI interventions in 161 patients, who received a structured follow-up thereafter. RESULTS: Receiver operating characteristic analyses, performed 6, 12, 24 and 48 months after TAVI, showed diffuse, but not focal, fibrosis as a significant predictor for SCD at all timepoints, with the highest area under the curve at the first time point and a decrease in its SCD predictivity over time. In both multivariate Cox proportional hazards and Fine-Gray competing risk models, including both fibrosis subtypes, as well as age, sex and ejection fraction, high diffuse fibrosis remained statistically significant. Accordingly, it represents an independent SCD predictor, most importantly for the occurrence of early events. CONCLUSIONS: The burden of diffuse cardiac fibrosis plays an important and independent prognostic role regarding SCD early after TAVI. Therefore, the histological evaluation of fibrosis topography has value as a prognostic tool for TAVI patients and may help to tailor individualised approaches to optimise their postinterventional management.

Proteome profiling of Campylobacter jejuni 81-176 at 37 °C and 42 °C by label-free mass spectrometry.

BACKGROUND: The main natural reservoir for Campylobacter jejuni is the avian intestinal tract. There, C. jejuni multiplies optimally at 42 °C - the avian body temperature. After infecting humans through oral intake, the bacterium encounters the lower temperature of 37 °C in the human intestinal tract. Proteome profiling by label-free mass spectrometry (DIA-MS) was performed to examine the processes which enable C. jejuni 81-176 to thrive at 37 °C in comparison to 42 °C. In total, four states were compared with each other: incubation for 12 h at 37 °C, for 24 h at 37 °C, for 12 h at 42 °C and 24 h at 42 °C. RESULTS: It was shown that the proteomic changes not only according to the different incubation temperature but also to the length of the incubation period were evident when comparing 37 °C and 42 °C as well as 12 h and 24 h of incubation. Altogether, the expression of 957 proteins was quantifiable. 37.1 - 47.3% of the proteins analyzed showed significant differential regulation, with at least a 1.5-fold change in either direction (i.e. log2 FC ≥ 0.585 or log2 FC ≤ -0.585) and an FDR-adjusted p-value of less than 0.05. The significantly differentially expressed proteins could be arranged in 4 different clusters and 16 functional categories. CONCLUSIONS: The C. jejuni proteome at 42 °C is better adapted to high replication rates than that at 37 °C, which was in particular indicated by the up-regulation of proteins belonging to the functional categories "replication" (e.g. Obg, ParABS, and NapL), "DNA synthesis and repair factors" (e.g. DNA-polymerase III, DnaB, and DnaE), "lipid and carbohydrate biosynthesis" (e.g. capsular biosynthesis sugar kinase, PrsA, AccA, and AccP) and "vitamin synthesis, metabolism, cofactor biosynthesis" (e.g. MobB, BioA, and ThiE). The relative up-regulation of proteins with chaperone function (GroL, DnaK, ClpB, HslU, GroS, DnaJ, DnaJ-1, and NapD) at 37 °C in comparison to 42 °C after 12 h incubation indicates a temporary lower-temperature proteomic response. Additionally the up-regulation of factors for DNA uptake (ComEA and RecA) at 37 °C compared to 42 °C indicate a higher competence for the acquisition of extraneous DNA at human body temperature.

Radiomics and machine learning for renal tumor subtype assessment using multiphase computed tomography in a multicenter setting.

OBJECTIVES: To distinguish histological subtypes of renal tumors using radiomic features and machine learning (ML) based on multiphase computed tomography (CT). MATERIAL AND METHODS: Patients who underwent surgical treatment for renal tumors at two tertiary centers from 2012 to 2022 were included retrospectively. Preoperative arterial (corticomedullary) and venous (nephrogenic) phase CT scans from these centers, as well as from external imaging facilities, were manually segmented, and standardized radiomic features were extracted. Following preprocessing and addressing the class imbalance, a ML algorithm based on extreme gradient boosting trees (XGB) was employed to predict renal tumor subtypes using 10-fold cross-validation. The evaluation was conducted using the multiclass area under the receiver operating characteristic curve (AUC). Algorithms were trained on data from one center and independently tested on data from the other center. RESULTS: The training cohort comprised n = 297 patients (64.3% clear cell renal cell cancer [RCC], 13.5% papillary renal cell carcinoma (pRCC), 7.4% chromophobe RCC, 9.4% oncocytomas, and 5.4% angiomyolipomas (AML)), and the testing cohort n = 121 patients (56.2%/16.5%/3.3%/21.5%/2.5%). The XGB algorithm demonstrated a diagnostic performance of AUC = 0.81/0.64/0.8 for venous/arterial/combined contrast phase CT in the training cohort, and AUC = 0.75/0.67/0.75 in the independent testing cohort. In pairwise comparisons, the lowest diagnostic accuracy was evident for the identification of oncocytomas (AUC = 0.57-0.69), and the highest for the identification of AMLs (AUC = 0.9-0.94) CONCLUSION: Radiomic feature analyses can distinguish renal tumor subtypes on routinely acquired CTs, with oncocytomas being the hardest subtype to identify. CLINICAL RELEVANCE STATEMENT: Radiomic feature analyses yield robust results for renal tumor assessment on routine CTs. Although radiologists routinely rely on arterial phase CT for renal tumor assessment and operative planning, radiomic features derived from arterial phase did not improve the accuracy of renal tumor subtype identification in our cohort.

Stable feature selection utilizing Graph Convolutional Neural Network and Layer-wise Relevance Propagation for biomarker discovery in breast cancer.

High-throughput technologies are becoming increasingly important in discovering prognostic biomarkers and in identifying novel drug targets. With Mammaprint, Oncotype DX, and many other prognostic molecular signatures breast cancer is one of the paradigmatic examples of the utility of high-throughput data to deliver prognostic biomarkers, that can be represented in a form of a rather short gene list. Such gene lists can be obtained as a set of features (genes) that are important for the decisions of a Machine Learning (ML) method applied to high-dimensional gene expression data. Several studies have identified predictive gene lists for patient prognosis in breast cancer, but these lists are unstable and have only a few genes in common. Instability of feature selection impedes biological interpretability: genes that are relevant for cancer pathology should be members of any predictive gene list obtained for the same clinical type of patients. Stability and interpretability of selected features can be improved by including information on molecular networks in ML methods. Graph Convolutional Neural Network (GCNN) is a contemporary deep learning approach applicable to gene expression data structured by a prior knowledge molecular network. Layer-wise Relevance Propagation (LRP) and SHapley Additive exPlanations (SHAP) are methods to explain individual decisions of deep learning models. We used both GCNN+LRP and GCNN+SHAP techniques to construct feature sets by aggregating individual explanations. We suggest a methodology to systematically and quantitatively analyze the stability, the impact on the classification performance, and the interpretability of the selected feature sets. We used this methodology to compare GCNN+LRP to GCNN+SHAP and to more classical ML-based feature selection approaches. Utilizing a large breast cancer gene expression dataset we show that, while feature selection with SHAP is useful in applications where selected features have to be impactful for classification performance, among all studied methods GCNN+LRP delivers the most stable (reproducible) and interpretable gene lists.

Short- and Long-Term Outcomes of Patients with Postoperative Arrhythmia after Liver Surgery.

BACKGROUND: New-onset postoperative arrhythmia (PA) has previously been described as a pivotal risk factor for postoperative morbidity and mortality after visceral surgery. However, there is a lack of data concerning liver surgery. The incidence and impact of new-onset postoperative arrhythmia after liver surgery was, therefore, analyzed in a monocentric study. METHODS: In total, n = 460 patients (221 female, 239 male) who underwent liver surgery between January 2012 and April 2020 without any prior arrhythmia in their medical history were included in this retrospective analysis. Clinical monitoring started with the induction of anesthesia and was terminated with discharge from the intensive care unit (ICU) or intermediate care unit (IMC). Follow-up included documentation of complications during the hospital stay, as well as long-term survival analysis. RESULTS: Postoperative arrhythmia after liver surgery was observed in 25 patients, corresponding to an incidence of 5.4%. The occurrence of arrhythmia was significantly associated with intraoperative complications (p < 0.05), liver fibrosis/cirrhosis (p < 0.05), bile fistula/bile leakage/bilioma (p < 0.05), and organ failure (p < 0.01). Survival analysis showed a significantly poorer overall survival of patients who developed postoperative arrhythmia after liver surgery (p < 0.001). CONCLUSIONS: New-onset postoperative arrhythmia after liver surgery has an incidence of only 5.4% but is significantly associated with higher postoperative morbidity and poorer overall survival.

The Increasing Prevalence of REM Sleep Behavior Disorder with Parkinson's Disease Progression: A Polysomnography-Supported Study.

Objectives: Rapid eye movement (REM) sleep behavior disorder (RBD) is proposed as an early diagnostic marker in Parkinson's disease (PD). We investigated the frequency of RBD during the progression of PD in the advanced stages and identified potential risk factors for developing RBD earlier or later. Patients and Methods: We performed a retrospective analysis and determined the frequency of RBD in all PD in-patients (Hoehn and Yahr stages ≥3) with motor fluctuations who had undergone video-polysomnography (vPSG) for a sleep complaint or daytime sleepiness. To correct for selection bias, we analyzed the prevalence of RBD in PD patients from the DeNoPa cohort. PD patients with RBD were compared with PD without RBD. To identify potential risk factors, we performed multiple regression modeling. Results: A total of 504 PD patients had vPSG. 37 were excluded due to missing REM or artifacts during REM. RBD was present in 406/467 (86.9%) PD patients. PD + RBD patients were older than PDnonRBD (69 ± 7.7 vs. 64 ± 9.2 years, P < 0.01), were more likely to have postural instability [234 (59.1%) vs. 19 (33.9%), P < 0.01], and were treated more often with antidepressants (other than SSRIs) [141 (34.7%) vs. 7 (13%), P < 0.01]. Multiple regression modeling identified predictors of RBD with an AUC of 0.78. Conclusion: The prevalence of RBD in patients with advanced PD is high and increases with disease severity, motor deficits, postural instability, orthostatic symptoms, and age. This suggests RBD is a progression marker of PD in patients with sleep complaints.

Postoperative facial appearance of patients with extensive oral squamous cell carcinoma can be adequately preserved with in­house virtually planned mandibular reconstruction.

The present study aimed to assess the concordance of preoperative and postoperative hard and soft tissues in patients with advanced oral squamous cell carcinoma (OSCC) following virtual surgical planning (VSP) mandibular reconstruction. In the present study, a cohort of 32 patients with OSCC underwent in-house VSP, followed by guided mandibular reconstruction utilizing vascularized free tissue grafts sourced from the fibula or scapula. A morphometric analysis was conducted comparing preoperative and postoperative three-dimensional virtual models to evaluate discrepancies and identify potential risk factors associated with poor reconstruction outcomes. The outcome variables were the differences in root mean square (RMS) and mean surface distance (MSD) resulting from the application of an iterative closest point algorithm to the virtual data. The validity of soft tissue comparison data is limited due to its susceptibility to various confounding variables. The present study conducted a comprehensive re-evaluation of these variables. High tumor stage, positive N status and the use of adjuvant therapy contributed to more noticeable differences in preoperative and postoperative facial soft tissue appearance. The accuracy of postoperative bone reconstruction results was higher in patients who underwent neomandibular formation using a fibular graft compared with those who received a scapular graft. Preoperative and postoperative soft tissue analyses were conducted for comparison. The MSD showed a deviation of 3.2 mm (± 2.0 mm SD; range 1.3-9.5 mm), whereas the RMS was 5.3 (± 2.9 SD; range 2.1-14). In conclusion, in-house VSP and guided mandibular reconstructions can yield clinically accurate results, preserving patient appearance and offering the advantage of rapid feasibility.

Humoral and cellular immune responses in fully vaccinated individuals with or without SARS-CoV-2 breakthrough infection: Results from the CoV-ADAPT cohort.

Despite recent advances in prophylactic vaccination, SARS-CoV-2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS-CoV-2 breakthrough infection is urgently needed. CoV-ADAPT is a prospective long-term study comparing humoral (anti-spike-RBD-IgG, neutralization capacity, avidity) and cellular (spike-induced T-cell interferon-γ [IFN-γ] release) immune responses in individuals vaccinated against SARS-CoV-2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS-CoV-2 breakthrough infections vs 151 without infection 3-7 months following third vaccination. Breakthrough infections significantly increased anti-spike-RBD-IgG (p < 0.01), but not spike-directed T-cell IFN-γ release (TC) or antibody avidity. Despite comparable surrogate neutralization indices, the functional neutralization capacity against SARS-CoV-2-assessed via a tissue culture-based assay-was significantly higher following breakthrough vs no breakthrough infection. Anti-spike-RBD-IgG and antibody avidity decreased with age (p < 0.01) and females showed higher anti-spike-RBD-IgG (p < 0.01), and a tendency towards higher antibody avidity (p = 0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p = 0.807). Finally, a machine-learning approach based on our large immunological dataset (a total of 49 variables) from different time points was unable to predict breakthrough infections (area under the curve: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g., virus exposure) in individualized risk assessment.

Combined Biomarker System Predicts Prognosis in Patients with Metastatic Oral Squamous Cell Carcinoma.

BACKGROUND: Metastatic oral squamous cell carcinoma (OSCC) is associated with poor patient prognosis. Metastasis is a complex process involving various proteins, tumor cell alterations, including changes attributable to the epithelial-to-mesenchymal transition (EMT) process, and interactions with the tumor microenvironment (TME). In this study, we investigate a combined protein marker system consisting of connexin 43 (Cx43), EMMPRIN (CD147), E-cadherin, and vimentin, with a focus on their roles in the invasive metastatic progression of OSCC and their potential utility in predicting prognosis. METHODS: We conducted an immunohistochemical analysis to assess the protein expression profiles of Cx43, EMMPRIN, E-cadherin, and vimentin using tissue samples obtained from 24 OSCC patients. The metastatic process was mapped through different regions of interest (ROIs), including adjacent healthy oral mucosa (OM), center of primary OSCC, invasive front (IF), and local cervical lymph node metastases (LNM). The primary clinical endpoints were disease-free survival (DFS) and overall survival (OS). RESULTS: Substantial changes in the expression profiles of the different marker proteins were observed among the different ROIs, with all p-values < 0.05, signifying statistical significance. Multivariable Cox regression analysis results showed a significant effect of increased EMMPRIN expression toward the IF on DFS (p = 0.019) and OS (p = 0.023). Furthermore, the combined predictive analysis showed a significant predictive value of the marker system for DFS (p = 0.0017) and OS (p = 0.00044). CONCLUSIONS: The combined marker system exhibited a significant ability to predict patient prognosis. An increase in EMMPRIN expression toward the IF showed the strongest effect and could be an interesting new antimetastatic therapy approach.

Does age matter?-Efficiency of mechanical food break down in Tupaia belangeri at different ages.

The relationship of food comminution and individual age in Tupaia belangeri is investigated. It is hypothesized that with increasing age the performance of the molar dentition decreases due to progressive tooth wear. While this relationship is well-documented for herbivores, age-related test series are largely lacking for insectivorous mammals. 15 individuals of Tupaia belangeri were fed exclusively with mealworms, and their faeces were analyzed for the number and size of chitin particles. The exoskeleton of a mealworm is resistant to digestive fluids in the gastrointestinal tract, and the size of individual chitin particles indicates the effectiveness of mechanical comminution that occurs in the oral cavity during mastication. It is hypothesized that a more precise occlusion of the dentition results in smaller particle size. Although individuals of all ages (juvenile, adult, and senile) were able to effectively process mealworms with their dentition prior to digestion, a larger area of very large chitin particles (98% quantile of all particles in senile animals as compared to in the same quantile in adults) in the feces of senile animals was detected. Even though the particle size of indigestible material is irrelevant for the digestive process, these findings either document somatic senescence in the functionality of the teeth, or alternatively a change in chewing behaviour with age.

Development and validation of explainable machine learning models for risk of mortality in transcatheter aortic valve implantation: TAVI risk machine scores.

Aims: Identification of high-risk patients and individualized decision support based on objective criteria for rapid discharge after transcatheter aortic valve implantation (TAVI) are key requirements in the context of contemporary TAVI treatment. This study aimed to predict 30-day mortality following TAVI based on machine learning (ML) using data from the German Aortic Valve Registry. Methods and results: Mortality risk was determined using a random forest ML model that was condensed in the newly developed TAVI Risk Machine (TRIM) scores, designed to represent clinically meaningful risk modelling before (TRIMpre) and in particular after (TRIMpost) TAVI. Algorithm was trained and cross-validated on data of 22 283 patients (729 died within 30 days post-TAVI) and generalisation was examined on data of 5864 patients (146 died). TRIMpost demonstrated significantly better performance than traditional scores [C-statistics value, 0.79; 95% confidence interval (CI)] [0.74; 0.83] compared to Society of Thoracic Surgeons (STS) with C-statistics value 0.69; 95%-CI [0.65; 0.74]). An abridged (aTRIMpost) score comprising 25 features (calculated using a web interface) exhibited significantly higher performance than traditional scores (C-statistics value, 0.74; 95%-CI [0.70; 0.78]). Validation on external data of 6693 patients (205 died within 30 days post-TAVI) of the Swiss TAVI Registry confirmed significantly better performance for the TRIMpost (C-statistics value 0.75, 95%-CI [0.72; 0.79]) compared to STS (C-statistics value 0.67, CI [0.63; 0.70]). Conclusion: TRIM scores demonstrate good performance for risk estimation before and after TAVI. Together with clinical judgement, they may support standardised and objective decision-making before and after TAVI.

Infection control strategies for healthcare workers during COVID-19 pandemic in German hospitals: A cross-sectional study in march-april 2021.

Background: Healthcare workers (HCW) are at risk of getting infected with COVID-19 at work. To prevent such incidents and provide a safe environment in hospitals, comprehensive infection control strategies are necessary. We aimed to collect information on COVID-19 infection control strategies regarding personal protective equipment (PPE), regulations during breaks for HCW and dissemination of pandemic-related information. Methods: We invited infection control practitioners from 987 randomly selected German hospitals in March-April 2021 to participate in our cross-sectional online survey. We categorized the hospital based on bed capacity (≤499 beds = small; ≥500 beds = large). Fisher's exact test was performed and p < 0.05 defined as statistically significant. Findings: 100 participants completed the questionnaire. Small hospitals were more directive about requiring FFP2 respirators (63%), whereas larger hospitals more often gave their HCW a choice between these and medical masks (67%). For the care of COVID-19 and suspected COVID-19 cases, >90% of the participants recommended the use of gloves. Notably, gloves were recommended beyond COVID-19 in 30% of the hospitals. During meal breaks various strategies were followed. Conclusion: Recommendations for PPE varied across hospital sizes, which could be due to different assessments of necessity and safety. Regulations during breaks varied strongly which illustrates the need for clear official guidelines.

Checkpoint blockade and BRAF/MEK therapy in the therapeutic setting improved the overall survival after sentinel node biopsy: A retrospective study comparing patients with primary care between 1998-2009 and 2010-2017.

Immunotherapies using checkpoint blockade and BRAF/MEK therapies have improved overall survival (OS) in patients with unresectable melanoma metastases. In this retrospective study, we aimed to demonstrate the resulting increase in melanoma-specific survival (MSS) and OS after the excision of primary melanomas (≥1 mm thick) and sentinel lymph node (SN) biopsy (SNB). Using Kaplan-Meier estimates and Cox models, we compared two consecutive cohorts. Patients in cohort 1 (N = 518) underwent SNB between 1998 and 2009, and patients in cohort 2 (N = 460) between 2010 and 2017, when checkpoint blockade and BRAF/(MEK) inhibition became available for the treatment of unresectable relapses. The median follow-up times were 120 and 73 months, respectively. While recurrence-free and distant metastasis-free survival rates remained very similar, MSS and OS increased in favor of cohort 2. The estimated 5-year OS rate of SN-positive patients increased by 14.3% (78.5% vs 64.2%, logrank test: P = .005). The MSS benefit was significant even with low SN tumor burden (metastasis diameter < 1 mm). On multivariate analyses, the risk-reduction in favor of cohort 2 was significant in the total population and in the SN-negative and SN-positive subgroups. In SN-positive patients, besides the availability of modern therapies, SN metastasis diameter and ulceration were independent factors of MSS and OS. Treatment of unresectable melanoma recurrences with modern drug therapies results in significantly higher survival rates in a population with SNB. The survival benefit measured from primary melanoma affects both the SN-positive and SN-negative subpopulations.

Incidence and impact of new-onset postoperative arrhythmia after surgery of the lower gastrointestinal tract.

Postoperative arrhythmias (PAs) are common events and have been widely investigated in cardiothoracic surgery. Within visceral surgery, a recent study revealed a significant occurrence of PA in esophageal resections. In contrast, PA in lower gastrointestinal surgery is rarely investigated and has been rudimentary described in the medical literature. The present work is a retrospective cohort study of 1171 patients who underwent surgery of lower gastrointestinal tract between 2012 and 2018. All included patients were treated and monitored in the intensive care unit (ICU) or intermediate care unit (IMC) after surgery. Follow-up, performed between January and May 2021, was obtained for the patients with PA investigating the possible persistence of PA and complications such as permanent arrhythmia or thromboembolic events after discharge. In total, n = 1171 patients (559 female, 612 male) without any history of prior arrhythmia were analyzed. Overall, PA occurred in n = 56 (4.8%) patients after surgery of the lower GI. The highest incidence of PA was seen in patients undergoing bowel surgery after mesenteric ischaemia (26.92%), followed by cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC; 16.67%). PA was significantly associated with higher age (72 years (IQR 63-78 years) vs. 64 years (IQR 55-73.5 years), p < 0.001) and longer length of stay in the ICU (median 15 days (IQR 5-25 days) vs. median 2 days (IQR 1-5 days), p < 0.001). PA was independently associated with organ failure (OR = 4.62, 95% CI 2.11-10.11, p < 0.001) and higher in-house mortality (OR = 3.37, 95% CI 1.23-9.28, p < 0.001). In median, PA occurred 66.5 h after surgery. In follow-up, 31% of all the patients with PA showed development of permanent arrhythmia. The incidence of PA after lower GI surgery is comparatively low. Its occurrence, however, seems to have severe implications since it is significantly associated with higher rates of organ failure and in-house mortality. Also, compared to the general population, the development of permanent arrhythmia is significantly higher in patients who developed new-onset PA.

Association of Overweight and Obesity With Bell Palsy in Children.

BACKGROUND: In the Division of Pediatric Neurology at the University Medical Center Göttingen we observed that many patients with Bell palsy are overweight or obese. To evaluate whether overweight and obesity are associated with increased risk of Bell palsy in children we conducted this single-centered retrospective study by performing a database search for International Classification of Diseases (ICD)-10 primary and secondary diagnosis of G51.0 (facial nerve palsy) between January 1, 2010, and December 31, 2020. METHODS: For risk assessment, patients' body mass indices (BMIs) were compared with BMI data of controls from a nationwide child health survey. RESULTS: In total, 202 patients with peripheral facial nerve palsies (pFPs) were included, of which nearly half were classified as Bell palsies; 38% and 24% of the patients with Bell palsy and pFP had a BMI above the 90th percentile, respectively. High BMI was associated with statistically increased odds of Bell palsy in the group of overweight and obese patients (BMI >90th percentile; odds ratio [OR], 2.42; 95% confidence interval [CI], 1.6 to 3.8; P < 0.001) and solely obese patients (BMI >97th percentile; OR, 2.43; 95% CI, 1.4 to 4.3; P = 0.003). CONCLUSIONS: We could confirm our observation that overweight and obesity are associated with increased risk of Bell palsy in children.

Cytogenetic peripheral blood monitoring in azacitidine treated patients with high-risk MDS/sAML: A monocentric real-world experience.

In this single center retrospective analysis 76 patients with high-risk (HR) myelodysplastic syndrome (MDS) treated with azacitidine (AZA) were reviewed for response, especially cytogenetic response (cyR) using repeated chromosome banding analyses (CBA) of bone marrow (bm) metaphases and frequent sequential Fluorescence-in-situ Hybridization (FISH) analyses of immunomagnetically enriched CD34 + circulating peripheral blood cells (CD34 +pb-FISH). In total, 526 CD34 +pb-FISH analyses and 236 CBA were examined. Median observation time was 8.45 months, median number of AZA cycles applied was 8, median overall survival (OS) was 14.9 months, 42.1 % of patients responded to therapy according to IWG criteria: 5 complete response (CR), 0 partial response (PR), 12 bmCR, 15 stable disease with hematologic improvement (HI). HI was reached in 36.8 % of patients, 31.5 % became transfusion-independent. By CBA or CD34 +pb-FISH 20.4 % and 31.6 % of patients showed cyR, respectively. HI rate was significantly higher in cytogenetic responders than in non-responders, but there was no impact on OS or leukemia-free-survival. Cytogenetic responders showed significantly better OS than non-responders. Patients with ≥ 6 AZA cycles had significantly better OS than patients with < 6 cycles applied. Karyotype evolution (KE) as a manifestation of cytogenetic progression was diagnosed in 29.5 % and 17.1 % of patients by CBA and CD34 +pb-FISH, respectively. KE was associated with significantly poorer OS and leukemia-free-survival.

Biomarker profiles in heart failure with preserved vs. reduced ejection fraction: results from the DIAST-CHF study.

AIMS: Chronic heart failure (HF) is a common disease and one of the leading causes of death worldwide. Heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF) are different diseases with distinct as well as comparable pathophysiologies and diverse responses to therapeutic agents. We aimed to identify possible pathobiochemical signalling pathways and biomarkers in HFpEF and HFrEF by using a broad proteomic approach. METHODS AND RESULTS: A total of 180 biomarkers in the plasma of a representative subgroup (71 years old) of HFpEF (70% female) with a left ventricular ejection fraction (LVEF) ≥ 50% and HFrEF (18% female) with an LVEF ≤ 40% patients (n = 127) from the Prevalence and Clinical Course of Diastolic Dysfunction and Diastolic Heart Failure (DIAST-CHF) trial were examined and compared with a healthy control group (n = 40; 48% female). We were able to identify 35 proteins that were expressed significantly different in both HF groups compared with the control group. We determine 29 unique proteins expressed in HFpEF and 33 unique proteins in HFrEF. Significantly up-regulated trefoil factor 3 (TFF3) and down-regulated contactin-1 could be identified as previously unknown biomarkers for HF. However, TFF3 is also a predictive factor for the occurrence of a cardiovascular event in HFpEF patients. In HFpEF, serine protease 27 was found at reduced levels for the first time, which could offer a new therapeutic target. Additionally, network analyses showed a special role of platelet-derived growth factor subunit A, Dickkopf-related protein 1, and tumour necrosis factor receptor superfamily member 6 in HFpEF patients, whereas perlecan and junctional adhesion molecule A stood out in the HFrEF group. Overall, signalling pathways of metabolic processes, cellular stress, and iron metabolism seemed to be important for HFrEF, whereas for HFpEF, oxygen stress, haemostasis, cell renewal, cell migration, and cell proliferation are in the foreground. CONCLUSIONS: The identified proteins and signalling pathways offer new therapeutic and diagnostic approaches for patients with chronic HF.

Influence of Shear Stress, Inflammation and BRD4 Inhibition on Human Endothelial Cells: A Holistic Proteomic Approach.

Atherosclerosis is an important risk factor in the development of cardiovascular diseases. In addition to increased plasma lipid concentrations, irregular/oscillatory shear stress and inflammatory processes trigger atherosclerosis. Inhibitors of the transcription modulatory bromo- and extra-terminal domain (BET) protein family (BETi) could offer a possible therapeutic approach due to their epigenetic mechanism and anti-inflammatory properties. In this study, the influence of laminar shear stress, inflammation and BETi treatment on human endothelial cells was investigated using global protein expression profiling by ion mobility separation-enhanced data independent acquisition mass spectrometry (IMS-DIA-MS). For this purpose, primary human umbilical cord derived vascular endothelial cells were treated with TNFα to mimic inflammation and exposed to laminar shear stress in the presence or absence of the BRD4 inhibitor JQ1. IMS-DIA-MS detected over 4037 proteins expressed in endothelial cells. Inflammation, shear stress and BETi led to pronounced changes in protein expression patterns with JQ1 having the greatest effect. To our knowledge, this is the first proteomics study on primary endothelial cells, which provides an extensive database for the effects of shear stress, inflammation and BETi on the endothelial proteome.