Oral rehabilitation and associated quality of life following mandibular reconstruction with free fibula flap: a cross-sectional study.

Introduction: Mandibular reconstruction with the free fibula flap (FFF) has become a standardized procedure. The situation is different with oral rehabilitation, so the purpose of this study was to investigate the frequency of implant placement and prosthetic restoration. Additionally, the patients' situation, motivation, and treatment course were structurally assessed. Materials and methods: All cases between January 2013 and December 2018 that underwent mandibular reconstruction in our department with a free fibula flap and gave written informed consent to participate were interviewed with two structured questionnaires about their restoration and quality of life. Additionally, medical records, general information, status of implants and therapy, and metric analyses of the inserted implants were performed. Results: In total 59 patients were enrolled and analyzed in this monocentric study. Overall, oral rehabilitation was achieved in 23.7% at the time of investigation. In detail, implants were inserted in 37.3% of patients and showed an 83.3% survival of dental implants. Of these implanted patients, dental implants were successfully restored with a prosthetic restoration in 63.6. Within this subgroup, satisfaction with the postoperative aesthetic and functional result was 79.9% and with the oral rehabilitation process was 68.2%. Satisfaction with the implant-borne prosthesis was 87.5%, with non-oral-squamous-cell-carcinoma patients being statistically significantly more content with the handling (p=0.046) and care (p=0.031) of the prosthesis. Discussion: Despite the well-reconstructed bony structures, there is a need to increase the effort of achieving oral rehabilitation, especially looking at the patient's persistent motivation for the procedure.

Tumor Contact With Internal Mammary Perforator Vessels as Risk Factor for Gross Internal Mammary Lymph Node Involvement in Patients With Breast Cancer.

PURPOSE: The identification of internal mammary lymph node metastases and the assessment of associated risk factors are crucial for adjuvant regional lymph node irradiation in patients with breast cancer. The current study aims to investigate whether tumor contact with internal mammary perforator vessels is associated with gross internal mammary lymph node involvement. METHODS AND MATERIALS: We included 297 patients with primary breast cancer and gross internal mammary (IMN+) and/or axillary metastases as well as 230 patients without lymph node metastases. Based on pretreatment dynamic contrast-enhanced magnetic resonance imaging, we assessed contact of the tumor with the internal mammary perforating vessels (IMPV). RESULTS: A total of 59 patients had ipsilateral IMN+ (iIMN+), 10 patients had contralateral IMN+ (cIMN+), and 228 patients had ipsilateral axillary metastases without IMN; 230 patients had node-negative breast cancer. In patients with iIMN+, 100% of tumors had contact with ipsilateral IMPV, with 94.9% (n = 56) classified as major contact. In iIMN- patients, major IMPV contact was observed in only 25.3% (n = 116), and 36.2% (n = 166) had no IMPV contact at all. Receiver operating characteristic analysis revealed that "major IMPV contact" was more accurate in predicting iIMN+ (area under the curve, 0.85) compared with a multivariate model combining grade of differentiation, tumor site, size, and molecular subtype (area under the curve, 0.65). Strikingly, among patients with cIMN+, 100% of tumors had contact with a crossing contralateral IMPV, whereas in cIMN- patients, IMPVs to the contralateral side were observed in only 53.4% (iIMN+) and 24.8% (iIMN-), respectively. CONCLUSIONS: Tumor contact with the IMPV is highly associated with risk of gross IMN involvement. Further studies are warranted to investigate whether this identified risk factor is also associated with microscopic IMN involvement and whether it can assist in the selection of patients with breast cancer for irradiation of the internal mammary lymph nodes.

SARS-CoV-2 Neutralization Capacity in Hemodialysis Patients with and without a Fifth Vaccination with the Updated Comirnaty Original/Omicron BA.4-5 Vaccine.

BACKGROUND: Hemodialysis patients have reduced serologic immunity after SARS-CoV-2 vaccination compared to the general population and an increased risk of morbidity and mortality when exposed to SARS-CoV-2. METHODS: Sixty-six hemodialysis patients immunized four times with the original SARS-CoV-2 vaccines (BNT162b2, mRNA-1273) either received a booster with the adapted Comirnaty Original/Omicron BA.4-5 vaccine 8.3 months after the fourth vaccination and/or experienced a breakthrough infection. Two months before and four weeks after the fifth vaccination, the live-virus neutralization capacities of Omicron variants BA.5, BQ.1.1, and XBB.1.5 were determined, as well as neutralizing and quantitative anti-SARS-CoV-2 spike-specific IgG antibodies. RESULTS: Four weeks after the fifth vaccination with the adapted vaccine, significantly increased neutralizing antibodies and the neutralization of Omicron variants BA.5, BQ.1.1, and XBB.1.5 were observed. The increase was significantly higher than after the fourth vaccination for variants BQ.1.1 and BA.5. Of all analyzed variants, BA.5 was neutralized best after the fifth vaccination. We did not see a difference in humoral immunity between the group with an infection and the group with a vaccination as a fifth spike exposure. Fivefold-vaccinated patients with a breakthrough infection showed a significantly higher neutralization capacity of XBB.1.5. CONCLUSION: A fifth SARS-CoV-2 vaccination with the adapted vaccine improves both wild-type specific antibody titers and the neutralizing capacity of the current Omicron variants BA.5, BQ.1.1, and XBB.1.5 in hemodialysis patients. Additional booster vaccinations with adapted vaccines will likely improve immunity towards current and original SARS-CoV-2 variants and are, therefore, recommended in hemodialysis patients. Further longitudinal studies must show the extent to which this booster vaccination avoids a breakthrough infection.

Akt-driven TGF-ß and DKK1 Secretion Impairs F508del CF Airway Epithelium Polarity.

Epithelial polarity is fundamental in maintaining barrier integrity and tissue protection. In cystic fibrosis (CF), apicobasal polarity of the airway epithelium is altered, resulting in increased apical fibronectin deposition and enhanced susceptibility to bacterial infections. Here, we evaluated the effect of highly effective modulator treatment (HEMT) on fibronectin apical deposition and investigated the intracellular mechanisms triggering the defect in polarity of the CF airway epithelium. To this end, primary cultures of CF (F508del variant) human airway epithelial cells (HAECs) and a HAEC line, Calu-3, knocked-down (KD) for CFTR (CFTR KD) were compared to control counterparts, grown at an air-liquid interface (ALI). We show that CFTR mutation in primary HAECs and CFTR KD cells promote the overexpression and over-secretion of TGF-ß1 and DKK1 when cultured at ALI. These dynamic changes result in hyperactivation of the TGF-ß pathway and inhibition of the Wnt pathway through degradation of ß-catenin leading to imbalanced proliferation and polarization. The abnormal interplay between TGF-ß and Wnt signaling pathways is reinforced by aberrant Akt signaling. Pharmacological manipulation of TGF-ß, Wnt, and Akt pathways restored polarization of the F508del CF epithelium, a correction that was not achieved by HEMT. Our data shed new insights into the signaling pathways that fine-tune apicobasal polarization in primary airway epithelial cells and may provide an explanation to the mitigated efficacy of HEMT on lung infection in people with CF.

Adherence and potential factors of adherence to a resistance, coordination and endurance training in older retirement home residents over 6 months.

INTRODUCTION: High exercise adherence is a key factor for effective exercise programmes. However, little is known about predictors of exercise adherence to a multimodal machine-based training in older retirement home residents. AIMS: To assess exercise adherence and potential predictors of adherence. Furthermore, to evaluate user acceptance of the multimodal training and the change in exercise self-efficacy. METHODS: In this sub-analysis of the bestform-F study, a total of 77 retirement home residents ≥65 years (mean age: 85.6 ± 6.6 years, 77.9% female) participated in a 6-month machine-based resistance, coordination and endurance training. Attendance to the training was documented for each training session. To identify potential predictors a multiple linear regression model was fitted to the data. Analyzed predictors included age, sex, body mass index (BMI), physical function, exercise self-efficacy, and physical activity history. Different domains of user acceptance (e.g. safety aspects, infrastructure) and exercise self-efficacy were assessed by a questionnaire and the exercise self-efficacy scale (ESES), respectively. RESULTS: Mean exercise adherence was 67.2% (median: 74.4%). The regression model (R2 = 0.225, p = 0.033) revealed that the 6-minute walk test (6-MWT) at baseline significantly predicted exercise adherence (ß: 0.074, 95% confidence interval (CI): 0.006-0.142, p = 0.033). Different user domains were rated at least as good by 83.9%-96.9% of participants, reflecting high acceptance. No statistically significant change was found for exercise self-efficacy over 6 months (mean change: 0.47 ± 3.08 points, p = 0.156). CONCLUSION: Retirement home residents attended more than two thirds of offered training sessions and physical function at baseline was the key factor for predicting adherence. User acceptance of the training devices was highly rated. These findings indicate good potential for implementation of the exercise programme.

COVID-19 in Female and Male Athletes: Symptoms, Clinical Findings, Outcome, and Prolonged Exercise Intolerance-A Prospective, Observational, Multicenter Cohort Study (CoSmo-S).

BACKGROUND: An infection with SARS-CoV-2 can lead to a variety of symptoms and complications, which can impair athletic activity. OBJECTIVE: We aimed to assess the clinical symptom patterns, diagnostic findings, and the extent of impairment in sport practice in a large cohort of athletes infected with SARS-CoV-2, both initially after infection and at follow-up. Additionally, we investigated whether baseline factors that may contribute to reduced exercise tolerance at follow-up can be identified. METHODS: In this prospective, observational, multicenter study, we recruited German COVID elite-athletes (cEAs, n = 444) and COVID non-elite athletes (cNEAs, n = 481) who tested positive for SARS-CoV-2 by PCR (polymerase chain reaction test). Athletes from the federal squad with no evidence of SARS-CoV-2 infection served as healthy controls (EAcon, n = 501). Questionnaires were used to assess load and duration of infectious symptoms, other complaints, exercise tolerance, and duration of training interruption at baseline and at follow-up 6 months after baseline. Diagnostic tests conducted at baseline included resting and exercise electrocardiogram (ECG), echocardiography, spirometry, and blood analyses. RESULTS: Most acute and infection-related symptoms and other complaints were more prevalent in cNEA than in cEAs. Compared to cEAs, EAcon had a low symptom load. In cNEAs, female athletes had a higher prevalence of complaints such as palpitations, dizziness, chest pain, myalgia, sleeping disturbances, mood swings, and concentration problems compared to male athletes (p < 0.05). Until follow-up, leading symptoms were drop in performance, concentration problems, and dyspnea on exertion. Female athletes had significantly higher prevalence for symptoms until follow-up compared to male. Pathological findings in ECG, echocardiography, and spirometry, attributed to SARS-CoV-2 infection, were rare in infected athletes. Most athletes reported a training interruption between 2 and 4 weeks (cNEAs: 52.9%, cEAs: 52.4%), while more cNEAs (27.1%) compared to cEAs (5.1%) had a training interruption lasting more than 4 weeks (p < 0.001). At follow-up, 13.8% of cNEAs and 9.9% of cEAs (p = 0.24) reported their current exercise tolerance to be under 70% compared to pre-infection state. A persistent loss of exercise tolerance at follow-up was associated with persistent complaints at baseline, female sex, a longer break in training, and age > 38 years. Periodical dichotomization of the data set showed a higher prevalence of infectious symptoms such as cough, sore throat, and coryza in the second phase of the pandemic, while a number of neuropsychiatric symptoms as well as dyspnea on exertion were less frequent in this period. CONCLUSIONS: Compared to recreational athletes, elite athletes seem to be at lower risk of being or remaining symptomatic after SARS-CoV-2 infection. It remains to be determined whether persistent complaints after SARS-CoV-2 infection without evidence of accompanying organ damage may have a negative impact on further health and career in athletes. Identifying risk factors for an extended recovery period such as female sex and ongoing neuropsychological symptoms could help to identify athletes, who may require a more cautious approach to rebuilding their training regimen. TRIAL REGISTRATION NUMBER: DRKS00023717; 06.15.2021-retrospectively registered.

Endovascular aortic repair with sac embolization for the prevention of type II endoleaks (the EVAR-SE study): study protocol for a randomized controlled multicentre study in Germany.

BACKGROUND: Beyond a certain threshold diameter, abdominal aortic aneurysms (AAA) are to be treated by open surgical or endovascular aortic aneurysm repair (EVAR). In a quarter of patients who undergo EVAR, inversion of blood flow in the inferior mesenteric artery or lumbar arteries may lead to type II endoleak (T2EL), which is associated with complications (e.g. AAA growth, secondary type I endoleak, rupture). As secondary interventions to treat T2EL often fail and may be highly invasive, prevention of T2EL is desirable. The present study aims to assess the efficacy of sac embolization (SE) with metal coils during EVAR to prevent T2EL in patients at high risk. METHODS: Over a 24-month recruitment period, a total of 100 patients undergoing EVAR in four vascular centres (i.e. Klinikum rechts der Isar of the Technical University of Munich, University Hospital Augsburg, University Hospital Dresden, St. Joseph's Hospital Wiesbaden) are to be included in the present study. Patients at high risk for T2EL (i.e. ≥ 5 efferent vessels covered by endograft or aneurysmal thrombus volume <40%) are randomized to one group receiving standard EVAR and another group receiving EVAR with SE. Follow-up assessments postoperatively, after 30 days, and 6 months involve contrast-enhanced ultrasound scans (CEUS) and after 12 months an additional computed tomography angiography (CTA) scan. The presence of T2EL detected by CEUS or CTA after 12 months is the primary endpoint. Secondary endpoints comprise quality of life (quantified by the SF-36 questionnaire), reintervention rate, occurrence of type I/III endoleak, aortic rupture, death, alteration of aneurysm volume, or diameter. Standardized evaluation of CTA scans happens through a core lab. The study will be terminated after the final follow-up visit of the ultimate patient. DISCUSSION: Although preexisting studies repeatedly indicated a beneficial effect of SE on T2EL rates after EVAR, patient relevant outcomes have not been assessed until now. The present study is the first randomized controlled multicentre study to assess the impact of SE on quality of life. Further unique features include employment of easily assessable high-risk criteria, a contemporary follow-up protocol, and approval to use any commercially available coil material. Overcoming limitations of previous studies might help SE to be implemented in daily practice and to enhance patient safety. TRIAL REGISTRATION: ClinicalTrials.gov NCT05665101. Registered on 23 December 2022.

Reduced tear fluid production in neurological diseases: a cohort study in 708 patients.

BACKGROUND: Tear fluid (TF) production is an important component of normal ocular function. It is regulated by parasympathetic and sympathetic innervation. Because parasympathetic nerve fibers originate in the brainstem, pathology in this brain region may affect TF production. For example, a reduction in TF production has been described in patients with Parkinson's disease (PD). METHODS: TF was collected at one center from 772 individuals, 708 of which were patients with different neurological diseases, and 64 healthy controls. Wetting lengths (WL) were recorded using Schirmer test strips with a collection time of 10 min. RESULTS: WL correlated negatively with age and was significantly reduced in subgroups of patients with neurodegenerative diseases (NDDs) (PD, Amyotrophic lateral sclerosis (ALS), other motor neuron diseases (MNDs)), as well as inflammatory/autoimmune/infectious central nervous system (CNS) diseases and vascular CNS diseases (VCDs), even if corrected for age or sex. While temperature had a significant negative effect on TF production, other environmental factors, such as hours of sunlight and humidity, did not. CONCLUSION: WL was altered in many neurological diseases compared to healthy controls. Most importantly, we observed a reduction of WL in NDDs, independent of age or sex. This study highlights the potential of WL as an easily obtainable parameter and suggests functional alterations in the autonomic innervation in various neurological disorders.

Long-Term Nephrotoxicity of 177Lu-PSMA Radioligand Therapy.

ß-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Platelet aggregates detected using quantitative phase imaging associate with COVID-19 severity.

BACKGROUND: The clinical spectrum of acute SARS-CoV-2 infection ranges from an asymptomatic to life-threatening disease. Considering the broad spectrum of severity, reliable biomarkers are required for early risk stratification and prediction of clinical outcomes. Despite numerous efforts, no COVID-19-specific biomarker has been established to guide further diagnostic or even therapeutic approaches, most likely due to insufficient validation, methodical complexity, or economic factors. COVID-19-associated coagulopathy is a hallmark of the disease and is mainly attributed to dysregulated immunothrombosis. This process describes an intricate interplay of platelets, innate immune cells, the coagulation cascade, and the vascular endothelium leading to both micro- and macrothrombotic complications. In this context, increased levels of immunothrombotic components, including platelet and platelet-leukocyte aggregates, have been described and linked to COVID-19 severity. METHODS: Here, we describe a label-free quantitative phase imaging approach, allowing the identification of cell-aggregates and their components at single-cell resolution within 30 min, which prospectively qualifies the method as point-of-care (POC) testing. RESULTS: We find a significant association between the severity of COVID-19 and the amount of platelet and platelet-leukocyte aggregates. Additionally, we observe a linkage between severity, aggregate composition, and size distribution of platelets in aggregates. CONCLUSIONS: This study presents a POC-compatible method for rapid quantitative analysis of blood cell aggregates in patients with COVID-19.

The human body produces a series of immune responses when it gets infected with SARS-CoV-2, the virus that causes COVID-19. One of these responses involves platelets, the blood clotting factor sticking to immune cells to form cell aggregates in the bloodstream. We aimed to understand the significance of these cell aggregates in COVID-19 disease progression. A quantitative imaging approach was used to investigate the number and components of these cell aggregates in SARS-CoV-2 infected patient blood. We observed blood from severe COVID-19 patients was associated with higher numbers and specific composition of cell aggregates. Our method can potentially support the risk stratification of severe patients to prevent complications in COVID-19 and other medical disorders, where immune cells are shown to aggregate.

High RIPK3 expression is associated with a higher risk of early kidney transplant failure.

Renal ischemia-reperfusion injury (IRI) is associated with reduced allograft survival, and each additional hour of cold ischemia time increases the risk of graft failure and mortality following renal transplantation. Receptor-interacting protein kinase 3 (RIPK3) is a key effector of necroptosis, a regulated form of cell death. Here, we evaluate the first-in-human RIPK3 expression dataset following IRI in kidney transplantation. The primary analysis included 374 baseline biopsy samples obtained from renal allografts 10 minutes after onset of reperfusion. RIPK3 was primarily detected in proximal tubular cells and distal tubular cells, both of which are affected by IRI. Time-to-event analysis revealed that high RIPK3 expression is associated with a significantly higher risk of one-year transplant failure and prognostic for one-year (death-censored) transplant failure independent of donor and recipient associated risk factors in multivariable analyses. The RIPK3 score also correlated with deceased donation, cold ischemia time and the extent of tubular injury.

Improved detection of infection with SARS-CoV-2 Omicron variants of concern in healthcare workers by a second-generation rapid antigen test.

IMPORTANCE: The results from this study demonstrate the usefulness of a second-generation rapid antigen test for early detection of infection with the SARS-CoV-2 Omicron variant of concern (VoC) and reveal a higher sensitivity to detect immune escape Omicron VoCs compared to a first-generation rapid antigen test (89.4% vs 83.7%) in the high-risk group of healthcare workers.

Antibiotic Treatment During Pregnancy and the First Six Months Postpartum - a Secondary Analysis of the "Healthy Living in Pregnancy" (GeliS) Study.

Introduction: Antibiotic therapies for the treatment of bacterial infections pose a particular challenge during pregnancy and breastfeeding. For Germany, there is hardly any information on the frequency of antibiotic use during this phase. Our analysis uses data from the "Healthy Living in Pregnancy" (GeliS) study to describe antibiotic treatments during pregnancy and in the first six months after birth (postpartum), and to compare their use with existing recommendations. Methods: This is a retrospective secondary analysis of the GeliS study. In the cluster randomized lifestyle intervention study, detailed information on antibiotic therapies during pregnancy and postpartum was collected using surveys. Chi-square tests and generalized estimating equations were used for evaluation. Results: Of the 1636 women included in the analysis, 21% reported antibiotic treatment at least once during pregnancy (14%) or in the first six months postpartum (7%). During pregnancy, the antibiotic therapies of women increased from 1.7% in the first trimester to 6.5% in the third trimester. Common reasons for treatment were urinary tract infections (7.3% of women), ear, nose, throat (ENT) infections (3.6%), and birth complications (2.6%). The information on the prescribed preparations corresponded to the current recommendations. A significant increase in the frequency of treatment with antibiotics was observed in the lifestyle intervention group (p < 0.001), in participants without a partner (p < 0.001), and in women who breastfed their children (p = 0.005) or gave birth by caesarean section (p = 0.003) or prematurely (p = 0.012). Other socioeconomic or lifestyle factors were not significant. Conclusion: Approximately one in five women receives at least one antibiotic treatment during pregnancy and breastfeeding that meets current treatment recommendations. Treatment with antibiotics is more common in premature births, caesarean sections, and breastfeeding women.

Influence of timing of Levosimendan administration on outcomes in cardiac surgery.

Purpose: Though a subgroup analysis has shown improved survival for patients suffering severely reduced ventricular function undergoing coronary artery bypass grafting, RCTs were not able to demonstrate overall beneficial effects of perioperative Levosimendan in cardiac surgery. This might be due to Levosimendan's pharmacokinetics reaching a steady-state concentration only 4-8 h after administration. Thus, this study now analysed the influence of timing of Levosimendan administration on perioperative outcome in cardiac surgery patients preoperatively presenting with severely reduced ventricular function and therefore considered at high-risk for intra- or postoperative low cardiac output syndrome. We hypothesized that prolonged preoperative Levosimendan administration ("preconditioning") would reduce mortality. Methods: All adult patients undergoing cardiac surgery between 2006 and 2018 perioperatively receiving Levosimendan were included in this retrospective, observational cohort study (n = 498). Patients were stratified into 3 groups: Levosimendan started on the day prior to surgery ("preop"), Levosimendan started on the day of surgery ("intraop") or post ICU admission ("postop"). After propensity score matching (PSM) was performed, outcomes defined according to proposed standard definitions for perioperative outcome research were compared between groups. Results: After PSM, there were no significant differences in patients' characteristics, comorbidities and type/priority of surgery between groups. Compared to intraop or postop Levosimendan treatment, preop treated patients had significantly lower in-hospital-mortality (preop vs. intraop. vs. postop = 16,7% vs. 33,3% vs. 42,3%), duration of mechanical ventilation and rate of continuous renal replacement therapy. Conclusions: Prolonged preoperative treatment with Levosimendan of cardiac surgery patients preoperatively presenting with severely reduced left ventricular function might be beneficial in terms of postoperative outcome. Our results are in line with recent experts' recommendations concerning the prolonged perioperative use of Levosimendan. We strongly recommend that future randomized trials include this "preconditioning" treatment as an experimental arm.

Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification.

Systemic pan-tumor analyses may reveal the significance of common features implicated in cancer immunogenicity and patient survival. Here, we provide a comprehensive multi-omics data set for 32 patients across 25 tumor types for proteogenomic-based discovery of neoantigens. By using an optimized computational approach, we discover a large number of tumor-specific and tumor-associated antigens. To create a pipeline for the identification of neoantigens in our cohort, we combine DNA and RNA sequencing with MS-based immunopeptidomics of tumor specimens, followed by the assessment of their immunogenicity and an in-depth validation process. We detect a broad variety of non-canonical HLA-binding peptides in the majority of patients demonstrating partially immunogenicity. Our validation process allows for the selection of 32 potential neoantigen candidates. The majority of neoantigen candidates originates from variants identified in the RNA data set, illustrating the relevance of RNA as a still understudied source of cancer antigens. This study underlines the importance of RNA-centered variant detection for the identification of shared biomarkers and potentially relevant neoantigen candidates.

Novel 5-aminopyrazoles endowed with anti-angiogenetic properties: Design, synthesis and biological evaluation.

The promising anti-angiogenetic properties of previously synthesized pyrazolyl ureas provided the rationale for the synthesis of novel 5-aminopyrazoles 2-5, differently decorated on the pyrazole nucleus. All the derivatives were tested by MTT assays and proved to be non-cytotoxic against eight different tumor cell lines and normal fibroblasts. An EdU proliferation assay was carried out on human foreskin fibroblasts and VEGF stimulated human umbilical vein endothelial cells which confirmed the absence of cytotoxicity of the compounds on human cells up to 20 µM concentration. To evaluate the influence of the newly synthesized pyrazoles on MAPK and PI3K signaling pathways, the phosphorylation of ERK1/2 and Akt was analyzed by Western blots from HFF and HUVEC cell lysates stimulated with growth factors in the presence or absence of the compounds. Pyrazoles 3b and 3c showed a significant inhibition of Akt phosphorylation in both tested cell lines with lower phosphorylation levels than the reference compound GeGe-3 in HUVEC. Furthermore, derivatives 2 and 3 appeared to strongly affect the migration of HFF cells in a wound healing assay, confirming their potential ability to interfere with the angiogenesis process. The new pyrazole library extends the structure-activity relationships of the previously isolated compounds and highlights the attractiveness of this chemical class for pathological cell migration and angiogenesis.

Novel Discovery of the Somatostatin Receptor (SSTR2) in Pleomorphic Adenomas via Immunohistochemical Analysis of Tumors of the Salivary Glands.

Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5-52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02-3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2-95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a 'strong' SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.