From molecular signatures to radiomics: tailoring neurooncological strategies through forecasting of glioma growth.

OBJECTIVE: Contemporary oncological paradigms for adjuvant treatment of low- and intermediate-grade gliomas are often guided by a limited array of parameters, overlooking the dynamic nature of the disease. The authors' aim was to develop a comprehensive multivariate glioma growth model based on multicentric data, to facilitate more individualized therapeutic strategies. METHODS: Random slope models with subject-specific random intercepts were fitted to a retrospective cohort of grade II and III gliomas from the database at Kepler University Hospital (n = 191) to predict future mean tumor diameters. Deep learning-based radiomics was used together with a comprehensive clinical dataset and evaluated on an external prospectively collected validation cohort from University Hospital Zurich (n = 9). Prediction quality was assessed via mean squared prediction error. RESULTS: A mean squared prediction error of 0.58 cm for the external validation cohort was achieved, indicating very good prognostic value. The mean ± SD time to adjuvant therapy was 28.7 ± 43.3 months and 16.1 ± 14.6 months for the training and validation cohort, respectively, with a mean of 6.2 ± 5 and 3.6 ± 0.7, respectively, for number of observations. The observed mean tumor diameter per year was 0.38 cm (95% CI 0.25-0.51) for the training cohort, and 1.02 cm (95% CI 0.78-2.82) for the validation cohort. Glioma of the superior frontal gyrus showed a higher rate of tumor growth than insular glioma. Oligodendroglioma showed less pronounced growth, anaplastic astrocytoma-unlike anaplastic oligodendroglioma-was associated with faster tumor growth. Unlike the impact of extent of resection, isocitrate dehydrogenase (IDH) had negligible influence on tumor growth. Inclusion of radiomics variables significantly enhanced the prediction performance of the random slope model used. CONCLUSIONS: The authors developed an advanced statistical model to predict tumor volumes both pre- and postoperatively, using comprehensive data prior to the initiation of adjuvant therapy. Using radiomics enhanced the precision of the prediction models. Whereas tumor extent of resection and topology emerged as influential factors in tumor growth, the IDH status did not. This study emphasizes the imperative of advanced computational methods in refining personalized low-grade glioma treatment, advocating a move beyond traditional paradigms.

Reduction of spondylolisthesis and restoration of lumbar lordosis after anterior lumbar interbody fusion (ALIF).

BACKGROUND: Anterior lumbar interbody fusion (ALIF) is a well-established surgical treatment option for various diseases of the lumbar spine, including spondylolisthesis. This study aimed to evaluate the postoperative correction of spondylolisthesis and restoration of lumbar and segmental lordosis after ALIF. METHODS: Patients with spondylolisthesis who underwent ALIF between 2013 and 2019 were retrospectively assessed. We assessed the following parameters pre-and postoperatively (6-months follow-up): Visual Analogue Scale (VAS) for pain, Oswestry Disability Index (ODI), lumbar lordosis (LL), segmental lordosis (SL), L4/S1 lordosis, and degree of spondylolisthesis. RESULTS: 96 patients were included. In 84 cases (87.50%), additional dorsal instrumentation was performed. The most frequent diagnosis was isthmic spondylolisthesis (73.96%). VAS was reduced postoperatively, from 70 to 40, as was ODI (50% to 32%). LL increased from 59.15° to 64.45°, as did SL (18.95° to 28.55°) and L4/S1 lordosis (37.90° to 44.00°). Preoperative spondylolisthesis was 8.90 mm and was reduced to 6.05 mm postoperatively. Relative spondylolisthesis was 21.63% preoperatively and 13.71% postoperatively. All clinical and radiological improvements were significant (all p < 0.001). No significant difference considering the lordosis values nor spondylolisthesis was found between patients who underwent ALIF surgery without dorsal instrumentation and patients who received additional dorsal instrumentation. Venous laceration was the most frequent complication (10.42%). CONCLUSIONS: With ALIF, good clinical results and safe and effective reduction of spondylolisthesis and restoration of lordosis can be achieved. Additional dorsal instrumentation does not significantly affect postoperative lordosis or spondylolisthesis. Individual vascular anatomy must be reviewed preoperatively before considering ALIF.

Preoperative application of the Enzian classification for endometriosis (The cEnzian Study): A prospective international multicenter study.

OBJECTIVE: To assess the diagnostic performance of preoperative application of the Enzian classification (cEnzian) using surgical findings as reference standard. DESIGN: A prospective international non-interventional study. SETTING: Twelve endometriosis centres in four European countries (Austria, Germany, Switzerland and Czech Republic). POPULATION: 1062 women with endometriosis surgery. METHODS: Extent of endometriosis was preoperatively classified using the cEnzian classification based on gynaecological examination and/or transvaginal ultrasound (TVS) and/or magnetic resonance imaging (MRI). After subsequent surgery, the surgeon classified the intraoperative findings using the Enzian classification. MAIN OUTCOME MEASURES: Sensitivity, specificity, PPV, NPV, LR+ , LR- and accuracy were calculated. Conditional frequencies of intraoperative Enzian codings and the corresponding 95% confidence intervals were computed for each preoperative coding and visualised in plots. RESULTS: Although overall consistency of cEnzian and Enzian was poor (35.14%, 95% confidence interval 32.26-38.03), high specificities and negative predictive values (NPVs) of the cEnzian compartments could be demonstrated. Looking at the individual parts of the Enzian classification, the poorest diagnostic performance was detected for compartment B and the highest PPVs were found for category 3 lesions (>3 cm), independent of the compartment. CONCLUSIONS: Using the Enzian classification in a non-invasive setting is a useful tool providing us with an 'at a glance' summary of the diagnostic workup regarding deep endometriosis with high specificities and NPVs. An attempt to merge the two new endometriosis classification systems (#Enzian and AAGL 2021) seems reasonable taking into consideration the respective advantages of each other.

Bleeding pattern after medical management of early pregnancy loss with mifepristone-misoprostol and its prognostic value: a prospective observational cohort study.

PURPOSE: To improve counseling of women by reporting bleeding characteristics at home after medical management of an early pregnancy loss (EPL) with mifepristone and misoprostol, and to evaluate occurring bleeding patterns as a prognostic tool. METHODS: This prospective two-center observational cohort study enrolled 197 women who presented with an EPL (embryonic or anembryonic miscarriage) from December 2017 to April 2019 and chose a home-based medical management with 200 mg mifepristone and 800 mcg misoprostol. From the day of mifepristone intake, the strength of vaginal bleeding was recorded daily for 2 weeks by the patient herself using a diary sheet. Treatment success was defined as no histologically confirmed retained products of conception (RPOC) within 3 months. After considering all drop-out criteria, 154 women were included in the analysis. RESULTS: 40.0% of patients (95% CI 30.4-49.6) already reported bleeding onset in the time period between the intake of mifepristone and misoprostol. The median duration of vaginal bleeding including spotting was 13 days. The chance of RPOC was about sixfold (OR 6.06, 95% CI 2.15-17.10) in the group of persistent bleeding after 2 weeks compared to the group with a terminated bleeding at that time. Exploratory regression analysis indicated association of higher serum levels of leukocytes at treatment start with RPOC (p = 0.013). CONCLUSIONS: Terminated bleeding after 2 weeks is a useful indicator for successful medical induction of EPL. Women undergoing medical treatment with mifepristone must be informed about the high frequency of bleeding onset before misoprostol intake. CLINICAL TRIAL REGISTRATION: DRKS-German Clinical Trials Register, ID: DRKS00013515, registration date 05.12.2017. http://www.drks.de/DRKS00013515 .

Frequency and characteristics of bacterial and viral low-grade infections of the intervertebral discs: a prospective, observational study.

STUDY DESIGN: Monocentric, prospective, observational study. OBJECTIVE: The clinical relevance of bacterial colonization of intervertebral discs is controversial. This study aimed to determine a possible relationship between bacterial and viral colonization and low-grade infection of the discs. METHODS: We investigated 447 disc samples from 392 patients. Microbiological culture was used to examine the samples for bacterial growth, polymerase chain reaction (PCR) was used for detection of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and Cytomegalovirus (CMV), and histopathological analysis was used to detect signs of inflammation. The results were compared between subgroups organized according to gender, age, location of the samples, surgical approach, preoperative C-reactive protein (CRP), preoperative and 6 months postoperative Oswestry Disability Index (ODI) and Neck Disability Index (NDI), and Modic changes (MC) of the corresponding endplates. Also, we assessed the occurrence of postoperative infections within 6 months. RESULTS: Microbiological culture was positive in 38.78% of the analyzed intervertebral discs. Altogether, 180 bacteria were isolated. Coagulase-negative staphylococci (CONS) (23.41%) and Cutibacterium acnes (18.05%) were the most frequently detected microorganisms. None of HSV-1, HSV-2, or CMV were detected. Male patients (p = 0.00036) and cervical segments (p = 0.00001) showed higher rates of positive culture results. Ventral surgical approaches ( p < 0.001) and Type 2 MC (p = 0.0127) were significantly associated with a positive microbiological result ( p< 0.001). Neither pre- nor postoperative ODI and NDI are associated with positive culture results. In 4 (1.02%) patients, postoperative spondylodiscitis occurred. CONCLUSIONS: With 447 segments from 392 patients, we present one of the largest studies to date. While disc degeneration caused by HSV-1, HSV-2, and CMV seems unlikely, we found positive microbiological culture results in 38.78% of all discs. The role of local skin flora and sample contamination should be the focus of further investigations. LEVEL OF EVIDENCE: III. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (ID: NCT04712487, https://www. CLINICALTRIALS: gov/ct2/show/study/NCT04712487 ).

Micropatterning as a tool to identify regulatory triggers and kinetics of actin-mediated endothelial mechanosensing.

Developmental processes, such as angiogenesis, are associated with a constant remodeling of the actin cytoskeleton in response to different mechanical stimuli. The mechanosensitive transcription factors MRTF-A (MKL1) and YAP (also known as YAP1) are important mediators of this challenging adaptation process. However, it is as yet unknown whether both pathways respond in an identical or in a divergent manner to a given microenvironmental guidance cue. Here, we use a micropatterning approach to dissect single aspects of cellular behavior in a spatiotemporally controllable setting. Using the exemplary process of angiogenesis, we show that cell-cell contacts and adhesive surface area are shared regulatory parameters of MRTF and YAP on rigid 2D surfaces. By analyzing MRTF and YAP under laminar flow conditions and during cell migration on dumbbell-shaped microstructures, we demonstrate that they exhibit different translocation kinetics. In conclusion, our work promotes the application of micropatterning techniques as a cell biological tool to study mechanosensitive signaling in the context of angiogenesis.

Cerebral oxygenation in 45-degree trendelenburg position for robot-assisted radical prostatectomy: a single-center, open, controlled pilot study.

BACKGROUND: Within the last decade, robotically-assisted laparoscopic prostatectomy (RALP) has become the standard for treating localized prostate cancer, causing a revival of the 45° Trendelenburg position. In this pilot study we investigated effects of Trendelenburg position on hemodynamics and cerebral oxygenation in patients undergoing RALP. METHODS: We enrolled 58 patients undergoing RALP and 22 patients undergoing robot-assisted partial nephrectomy (RAPN) (control group) in our study. Demographic patient data and intraoperative parameters including cerebral oxygenation and cerebral hemodynamics were recorded for all patients. Cerebral function was also assessed pre- and postoperatively via the Mini Mental Status (MMS) exam. Changes in parameters during surgery were modelled by a mixed effects model; changes in the MMS result were evaluated using the Wilcoxon signed rank test. RESULTS: Preoperative assessment of patient characteristics, standard blood values and vital parameters revealed no difference between the two groups. CONCLUSIONS: Applying a 45° Trendelenburg position causes no difference in postoperative brain function, and does not alter cerebral oxygenation during a surgical procedure lasting up to 5 h. Further studies in larger patient cohorts will have to confirm these findings. TRIAL REGISTRATION: German Clinical Trial Registry; DRKS00005094; Registered 12th December 2013-Retrospectively registered; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00005094 .

SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy.

Cardiac functionality is dependent on a balanced protein turnover. Accordingly, regulated protein decay is critical to maintain cardiac function. Here we demonstrate that deficiency of SPRED2, an intracellular repressor of ERK-MAPK signaling markedly expressed in human heart, resulted in impaired autophagy, heart failure, and shortened lifespan. SPRED2-/- mice showed cardiomyocyte hypertrophy, cardiac fibrosis, impaired electrical excitability, and severe arrhythmias. Mechanistically, cardiomyocyte dysfunction resulted from ERK hyperactivation and dysregulated autophagy, observed as accumulation of vesicles, vacuolar structures, and degenerated mitochondria. The diminished autophagic flux in SPRED2-/- hearts was reflected by a reduced LC3-II/LC3-I ratio and by decreased Atg7, Atg4B and Atg16L expression. Furthermore, the autophagosomal adaptors p62/SQSTM1 and NBR1 and lysosomal Cathepsin D accumulated in SPRED2-/- hearts. In wild-type hearts, SPRED2 interacted physically with p62/SQSTM1, NBR1, and Cathepsin D, indicating that SPRED2 is required for autophagolysosome formation in regular autophagy. Restored inhibition of MAPK signaling by selumetinib led to an increase in autophagic flux in vivo. Therefore, our study identifies SPRED2 as a novel, indispensable regulator of cardiac autophagy. Vice versa, SPRED2 deficiency impairs autophagy, leading to cardiac dysfunction and life-threatening arrhythmias.

Iron status determination in individuals with Helicobacter pylori infection: conventional vs. new laboratory biomarkers.

Background Helicobacter pylori has been associated with iron deficiency (ID). This study is aimed at investigating ID with conventional (ferritin, transferrin saturation [TSAT]) and new biomarkers (soluble transferrin receptor [sTfR], sTfR/log ferritin, reticulocyte hemoglobin content [CHr], hepcidin-25) in patients sub-grouped by the presence or absence of H. pylori infection. Methods In total, 200 consecutive outpatients, who were referred for the H. pylori 13C-urea breath test (13C-UBT), underwent blood testing for ID. Additionally, Thomas-plot (TP)-analyses (sTfR/log ferritin, CHr) were calculated. Results Fifty-three and 147 individuals were found with and without H. pylori infection, respectively. Patients with H. pylori infection showed a higher sTfR concentration (p<0.02) and a higher sTfR/log ferritin ratio (p<0.05). Based on a ferritin <30 µg/L and/or a TSAT <20%, 25/53 (47.2%) patients with H. pylori infection and 63/147 (42.9%) without H. pylori infection showed ID. Based on TP-analyses, 10/53 (18.9%) patients with and 17/147 (11.6%) without H. pylori infection were identified with ID. Completed eradication therapy tended to be associated with functional ID. Conclusions Helicobacter pylori infection was associated with significantly higher plasma sTfR concentrations and sTfR/log ferritin ratios. Patients with H. pylori eradication therapy were more often detected with functional ID compared to patients without eradication therapy, when using the new biomarkers.

Long-term mortality rates in pediatric hydrocephalus-a retrospective single-center study.

PURPOSE: Very long-term follow-up and outcome are rare for pediatric patients with hydrocephalus and shunt operations. The aim of this study was to determine the long-term mortality rates in these patients. METHODS: Pediatric patients with first shunt operation between 1982 and 1992 were included. For each patient, time and cause of death were determined. Further, patients with first operation from 1982 to 1987 were compared to those first operated from 1988 to 1992. RESULTS: One-hundred thirty-seven patients were included. Etiologies of hydrocephalus were intraventricular hemorrhage (31.4 %), meningomyelocele (25.5 %), postinfectious (11.7 %), congenital (10.2 %), posterior fossa cyst (8.8 %), aqueductal stenosis (8 %), and others (4.4 %). Overall, 53 patients (38.7 %) died. The percentage of patients surviving 1, 2, 10, and 20 years after first operation were 82.6, 73.6, 69.4, and 65.3 %, respectively. In 23 patients, the cause of death was related to shunt treatment: shunt infection was diagnosed in 18 and acute shunt dysfunction in 5 patients. Mortality was considerably higher for patients with their first operation in time period 1982-1987 compared to time period 1988-1992 (51 versus 25 %). The reduction of mortality was mainly due to an increased survival after shunt infection. Eighty-seven patients survived more than 20 years after initial shunt operation. Of those long-term survivors, three (3.4 %) patients died 22-24 years after first operation. CONCLUSION: Mortality in hydrocephalic pediatric patients is high especially in the first postoperative years but is even significant in adult patients with pediatric hydrocephalus. As deaths occur even after 20 years, routine follow-up of long-term survivors remains necessary.

Hepcidin-25 vs. conventional clinical biomarkers in the diagnosis of functional iron deficiency.

OBJECTIVES: As hepcidin-25 is considered as a key regulator of human iron homoeostasis, this study aimed to compare this parameter with conventional biomarkers and diagnostic tools of iron deficiency (ID). METHODS: In total, 233 hospitalised adult patients, who underwent routine blood testing for ID, were included. All subjects were investigated for hepcidin-25, reticulocyte haemoglobin content (CHr), soluble transferrin receptor (sTfR)/log ferritin ratio (i.e. Thomas plot), sTfR, ferritin, transferrin saturation (TSAT), C-reactive protein (CRP) and for complete blood cell count. Functional ID was defined as a CHr < 28 pg. Separate logistic regression models were calculated with all potential biomarkers to evaluate and compare the predictive performance with respect to functional ID in patients without (CRP ≤ 0.5 mg/dL) and with (CRP > 0.5 mg/dL) acute-phase reaction, respectively. RESULTS: One hundred seventeen patients with CRP > 0.5 mg/dL showed a distinctly higher hepcidin-25 median value [35.60 (range: 4.27-80.03) ng/mL] as compared to 116 patients with CRP ≤ 0.5 mg/dL [18.55 (range: 3.77-73.01) ng/mL]. With respect to functional ID, sTfR/log ferritin ratio and sTfR were of better positive predictive value (PPV) (sTfR/log ferritin ratio: 58.33% and 70.83%; sTfR: 60.00% and 60.00%) than when compared to hepcidin-25 (PPV: 37.74% and 42.86%) and ferritin (PPV: 27.54% and 46.15%) in both subgroups. CONCLUSIONS: The sTfR/log ferritin ratio, as well as sTfR, were better predictors of functional ID in patients with and without acute-phase reaction as compared to hepcidin-25 and ferritin.

Screening for depression in epilepsy: a model of an enhanced screening tool.

OBJECTIVE: Depression is common but frequently underdiagnosed in people with epilepsy. Screening tools help to identify depression in an outpatient setting. We have published validation of the NDDI-E and Emotional Thermometers (ET) as screening tools for depression (Rampling et al., 2012). In the current study, we describe a model of an optimized screening tool with higher accuracy. METHODS: Data from 250 consecutive patients in a busy UK outpatient epilepsy clinic were prospectively collected. Logistic regression models and recursive partitioning techniques (classification trees, random forests) were applied to identify an optimal subset from 13 items (NDDI-E and ET) and provide a framework for the prediction of class membership probabilities for the DSM-IV-based depression classification. RESULTS: Both logistic regression models and classification trees (random forests) suggested the same choice of items for classification (NDDI-E item 4, NDDI-E item 5, ET-Distress, ET-Anxiety, ET-Depression). The most useful regression model includes all 5 mentioned variables and outperforms the NDDI-E as well as the ET with respect to AUC (NDDI-E: 0.903; ET7: 0.889; logistic regression: 0.943). A model developed using random forests, grown by restricting the possible splitting of variables to these 5 items using only subsets of the original data for single classification, performed similarly (AUC: 0.949). CONCLUSIONS: For the first time, we have created a model of a screening tool for depression containing both verbal and visual analog scales, with characteristics supporting that this will be more precise than previous tools. Collection of a new data sample to assess out-of-sample performance is necessary for confirmation of the predictive performance.

Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction.

Myocardial infarction (MI) leads to rapid necrosis of cardiac myocytes. To achieve tissue integrity and function, inflammatory cells are activated, including monocytes/macrophages. However, the effect of monocyte/macrophage recruitment after MI remains poorly defined. After experimental MI, monocytes and macrophages were depleted through serial injections of clodronate-containing liposomes. Monocyte/macrophage infiltration was reduced in the myocardium after MI by active treatment. Mortality was increased due to thromboembolic events in monocyte- and macrophage-depleted animals (92 vs. 33%; P<0.01). Left ventricular thrombi were detectable as early as 24 h after MI; this was reproduced in a genetic model of monocyte/macrophage ablation. A general prothrombotic state, increased infarct expansion, and deficient neovascularization were not observed. Severely compromised extracellular matrix remodeling (collagen I, placebo liposome vs. clodronate liposome, 2.4 ± 0.2 vs. 0.8 ± 0.2 arbitrary units; P<0.001) and locally lost integrity of the endocardium after MI are potential mechanisms. Patients with a left ventricular thrombus had a relative decrease of CD14CD16 monocyte/macrophage subsets in the peripheral blood after MI (no thrombus vs. thrombus, 14.2 ± 0.9 vs. 7.80 ± 0.4%; P<0.05). In summary, monocytes/macrophages are of central importance for healing after MI. Impaired monocyte/macrophage function appears to be an unrecognized new pathophysiological mechanism for left ventricular thrombus development after MI.

SARS-CoV-2 vaccination willingness and humoral vaccination response in radiation oncology patients.

BACKGROUND: SARS-CoV-2 infection has been and, in some parts, still is a threat to oncologic patients, making it crucial to understand perception of vaccination and immunologic responses in this vulnerable patient segment. SARS-CoV-2 vaccines in relation to malignant disease characteristics and therapies have so far not been studied consecutively in larger oncologic patient populations. This study captures SARS-CoV-2 vaccination willingness and humoral immune response in a large consecutive oncologic patient collective at the beginning of 2021. METHODS: 1142 patients were consecutively recruited over 5.5 months at a tertiary department for radiation oncology and were assessed for vaccination willingness via a standardized interview. In already vaccinated patients total SARS-CoV-2 S antibody titres against the spike protein (Anti-SARS-CoV-2 S) and were evaluated 35 days or later after the first dose of SARS-CoV-2 vaccine. RESULTS: Vaccination willingness was high with a rate of 90 %. The most frequent reasons for rejection were: undecided/potential vaccination after therapy, distrust in the vaccine and fear of interaction with comorbidities. Factors associated with lower vaccination willingness were: worse general condition, lower age and female sex. 80 % of the participants had been previously vaccinated, 8 % reported previous infection and 16 % received vaccination during antineoplastic therapy. In 97.5 % of the vaccinated patients Anti-SARS-CoV-2 S was detected. In a univariable analysis parameters associated with non-conversion were: lower performance status, spread to the local lymphatics (N + ), hematologic disease and diffuse metastases. All patients with oligometastatic disease achieved positive Anti-SARS-CoV-2 S titres. For patients with two vaccinations several risk factors were identified, that were associated with low antibody concentrations. CONCLUSIONS: SARS-CoV-2 vaccination willingness among oncologic patients was high in the first months after its availability, and most patients had already received one or two doses. Over 97 % of vaccinated patients had measurable anti-SARS-CoV-2 S titres. Our data supports early identification of low humoral responders after vaccination and could facilitate the design of future oncologic vaccine trials (clinicaltrials.gov Identifier: NCT04918888).

Mena/VASP and αII-Spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy.

BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and ß-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, ß-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired. CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted ß-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.

Can Classifications Adequately Represent Genital Malformations?: EVA Study ( E SHRE/ESGE | V CUAM | A FS) - A Prospective Multicenter Study to Evaluate the Current Female Genital Malformation Classifications.

Introduction Genital malformations are a common clinical occurrence that can be represented using different classifications. Reproducibility is an essential quality characteristic for a classification, and it plays an important role, especially in consultations and the treatment of infertile patients and in obstetric management. The aim of this study is to demonstrate the reproducibility and clinical practicality of three commonly used classifications: the ESHRE/ESGE (European Society of Human Reproduction and Embryology/ European Society for Gynecological Endoscopy), VCUAM (Vagina Cervix Uterus Adnex-associated Malformation), and AFS (American Fertility Society) classifications. Materials and Methods Sixty-five patients with female genital malformations were included in this prospective, multicenter, exploratory, observational study. All participants underwent a clinical examination and a medical interview. The investigators were instructed to classify the presenting malformations according to the ESHRE/ESGE, VCUAM, and AFS classifications using a structured questionnaire. Investigators were asked whether the malformation could be reproducibly classified (yes/no) and about the grade (grade 1-5 from "very good" to "deficient") they would assign to each classification. Classification assessment was queried for vagina, cervix, uterus, adnexa, and associated malformations and was scored from 1 to 5. Results Reproducibility was rated as 80% (n = 52/65), 92.3% (n = 60/65), and 56.9% (n = 37/65) for the ESHRE/ESGE, VCUAM, and AFS classification, respectively. ESHRE/ESGE, VCUAM and AFS were rated as "very good" or "good" for 83.3%, 89.2%, and 10.8% of vaginal malformations; for 75.8%, 87.5%, and 24.2% of cervical malformations; and for 89.7%, 89.5%, and 86.2% of uterine malformations, respectively. VCUAM was rated as "very good" or "good" for 77.8% and 69.6% of adnexal malformations and associated malformations, respectively. ESHRE/ESGE and AFS were rated as "sufficient" or "deficient" for 100% and 75% of adnexal malformations and for 77.3% and 69.6% of associated malformations, respectively. Conclusion The prospective multicenter EVA ( E SHRE/ESGE | V CUAM | A FS) study revealed that the organ-based ESHRE/ESGE and VCUAM classifications of female genital malformations perform better in terms of reproducibility as well as in the assessment of individual compartments than the non-organ-based AFS classification.

Steroids for the treatment of viral encephalitis: a systematic literature review and meta-analysis.

BACKGROUND: Specific antiviral treatment is only available for a small subset of viral encephalitis (VE). Adjunctive steroids are used, but there is scant evidence evaluating its utility. We present a systematic review and meta-analysis on the outcome of steroid use in VE. METHODS: We conducted a systematic literature review and reported it according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Two observational studies from unpublished or partially published data were added. For the meta-analysis, we employed the metaphor package of the statistical software R-4.3.1. RESULTS: We screened 378 studies and included 50. 155 patients were added from the Houston and Linz cohorts. Individual data were available for 281 persons, 120 (43%) of whom received steroids. The most common pathogens were herpes simplex virus 1, West Nile virus, and measles. Study designs and patient outcomes were heterogeneous. Only three of the trials report an advantage of steroid therapy. Steroid-induced side effects were scarce. Ten cohorts were included into the meta-analysis. For the pooled data, the null hypothesis could not be rejected (p = 0.245) using a random effects model, i.e., a benefit of steroid treatment on survival in VE could not be shown. CONCLUSIONS: Steroids as potent anti-inflammatory agents may act through a reduction of secondary inflammation-mediated damage. Our data do not support the use of steroids in VE. However, multiple shortcomings apply. Standardized controlled trials are needed to investigate optimal dosing and timing of steroid administration and to explore potential subgroups that could benefit.

A comparative study of various prism adaptation forms in the surgical management of esophoria.

PURPOSE: To evaluate the outcome in participants who underwent surgery for esophoria following one of three different methods of preoperative prism adaptation test (PAT). METHODS: This prospective, multicentre study was carried out at five eye departments from 2012 to 2019. 116 participants were included and allocated to three groups as per investigator choice: Group 1 (n = 55) had a short prism adaptation period ranging from 1 to 5 hours during their visit at the clinic. Group 2 (n = 36) underwent partial prism correction for at least 4 weeks before surgery. Group 3 (n = 25) underwent full prism correction for at least 4 weeks before surgery. Motoric success was determined by postoperative angle of deviation (AOD), and sensoric success was evaluated with Lang and Bagolini striated lens test. RESULTS: A significant increase (p < 0.001) in AOD after PAT was observed in all groups, with no significant difference between groups (distance: p = 0.22; near: p = 0.31). Motoric and sensoric success was comparable between groups 3 months (p = 0.52; p = 0.55) and 1 year (p = 0.53; p = 0.29) after surgery. Prolonged prism adaptation (n = 24) for more than 365 days was not associated with better results. CONCLUSION: Our study indicates that the postoperative result is independent from the duration and amount (partial or full correction) of prism adaptation before surgery at least up to one year of follow-up. Prolonged prism adaptation (>365 days) before surgery does not improve the results.

Identification of Dermatophyte and Non-Dermatophyte Agents in Onychomycosis by PCR and DNA Sequencing-A Retrospective Comparison of Diagnostic Tools.

Rapid and reliable fungal identification is crucial to delineate infectious diseases, and to establish appropriate treatment for onychomycosis. Compared to conventional diagnostic methods, molecular techniques are faster and feature higher accuracy in fungal identification. However, in current clinical practice, molecular mycology is not widely available, and its practical applicability is still under discussion. This study summarizes the results of 16,094 consecutive nail specimens with clinical suspicion of onychomycosis. We performed PCR/sequencing on all primary nail specimens for which conventional mycological diagnostics remained inconclusive. In specimens with a positive direct microscopy but negative or contaminated culture, molecular mycology proved superior and specified a fungal agent in 65% (587/898). In 75% (443/587), the identified pathogen was a dermatophyte. Positive cultures for dermatophytes, yeasts and non-dermatophyte molds (NDMs) were concordant with primary-specimen-DNA PCR/sequencing in 83% (10/12), 34% (22/65) and 45% (76/169), respectively. Among NDMs, agreement was high for Fusarium spp. (32/40; 80%), but low for Penicillium spp. (5/25; 20%) and Alternaria spp. (1/20; 5%). This study underlines the improvement in diagnostic yield by fungal primary-specimen-DNA PCR/sequencing in the event of a negative or contaminated culture, as well as its significance for the diagnosis of dermatophyte and non-dermatophyte onychomycosis. Molecular mycology methods like PCR and DNA sequencing should complement conventional diagnostics in cases of equivocal findings, suspected NDM onychomycosis or treatment-resistant nail pathologies.

NT-pro-BNP as a Predictor for Recurrence of Atrial Fibrillation after Primary Cryoballoon Pulmonary Vein Isolation.

NT-pro-BNP is produced in the cardiac atria and ventricles in response to increased wall stress. It may be a marker of both AF disease progression and co-morbidities that affect success after pulmonary vein isolation (PVI). This single-center retrospective study analyzed the association between pre-procedural NT-pro-BNP serum levels and the long-term outcome after a first-ever PVI in cryo-technique. Patients were followed by searching the hospital information system and conducting structured telephone interviews. Treatment failure was defined as any relapse of atrial fibrillation (AF) occurring 90 days after the index PVI at the earliest. Kaplan−Meier survival curves and Cox proportional hazards models were computed to assess the impact of NT-pro-BNP on AF recurrence. Following 374 patients over a median of 3.8 years (range: 0.25−9.4 years), baseline NT-pro-BNP was associated with the combined endpoint in univariate analysis (HR 1.04 per 100 pg/mL increase, 95% CI: 1.02−1.07, p < 0.001). Results were virtually unchanged in the multivariate model or if the data were log-transformed. Intraprocedural left atrial pressure correlated positively with log NT-pro-BNP. NT-pro-BNP was associated with AF relapse during a long-term follow-up after first-ever cryo-PVI in our cohort of patients with predominantly normal left ventricular function. This lab parameter is easy to obtain and has significant potential to guide treatment decisions.