Background: Cytogenetic testing (CGT) in uveal melanoma patients reveals prognostic information about the individual risk of developing distant metastasis with dismal prognosis. There is currently no medical intervention strategy with proven effect on the prognosis, rendering the result of the cytogenetic testing purely informative. We explored patients' socio-demographic backgrounds, psychological preconditions, coping strategies, external influences, and concerns about "knowing their fate" to study their possible interactions with decision-making for CGT.

Methods: Uveal melanoma patients were asked to complete questionnaires on their interest in undergoing CGT for prognostication and the factors influencing their decision. Data were collected on socio-demographics, baseline anxiety (GAD-7), depression (PHQ-9), coping strategies (Brief COPE), and assumed future concerns regarding the CGT result. Data were analyzed by using multiple ordinal logistic regression and exploring estimated marginal effects.

Results: Questionnaires were returned by 121 of 131 (92.4%) patients. Fifty-two patients (43%) had no interest in CGT, 34 (28.1%) were undecided, and 35 (28.9%) were interested. We observed no significant differences regarding age, sex, partnership, education, occupation, baseline anxiety, or depression. Decision-making favoring CGT was influenced by the treating physicians, internet resources, and level of baseline anxiety. Patients were likely to reject CGT when they worried that "knowing the result will have an unintended influence" on their life.

Conclusion: Decision-making about CGT for prognostication in uveal melanoma is burdensome to many patients and in general not guided by medical advice regarding further treatment and screening procedures. The psychological impact of the decision is therefore unique and requires careful support by psycho-oncologists considering the patient's fears and expectations.

In order to achieve optimal results, competitive athletes are exposed to high physical and mental demands. For this, the function of the regeneration phase is also important, to which a restorative sleep contributes significantly. However, there are indications that insomnia symptoms may occur frequently in competitive athletes due to various stressors during training and competitions. Competitive athletes (LS) and a group of healthy controls (GK) were studied with a home sleep test (HST) in order to objectively investigate sleep structure, sleep quality, and the function of the cardiac autonomic tone. An HST including 1-lead EEG, 2-lead EOG, SpO2, and 1-lead ECG (SOMNOtouch (TM), Somnomedics) was successfully performed for group LS in n = 12 subjects (age 25.1 +/- 4.3 years) and for group GK in n = 17 subjects (age 26.1 +/- 3.2 years), each containing females and males. Questionnaires were applied to assess daytime sleepiness (Epworth Sleepiness Scale, ESS), insomnia severity (Insomnia Severity Index, ISI), and symptoms for sleep apnea (actualized STOP-Bang Questionnaire, aSBF). Sleep stages were scored visually and heart rate and heart rate variability (HRV) parameters were calculated from ECG using time series analysis (DOMINO light, Somnomedics). Data analysis revealed no differences between groups LS and GK regarding ESS and aSBF, although ISI was increased in group LS compared to GK (5.7 +/- 4.1 vs. 2.4 +/- 2.0; p < 0.02). In evaluation of sleep structure, no differences were found for sleep onset latency (ESL), total sleep time (TST), and sleep efficiency (SE) as well as percentages of light (N1 + N2), deep (N3), and REM (REM) sleep. Time in bed (TIB) was increased in group LS (503.2 +/- 52.7 vs. 445.5 +/- 45.4 min; p < 0.02). Comparing group LS with group GK it was found that mean nocturnal heart rate was decreased (48.5 +/- 6.8 vs. 56.1 +/- 5.4; p < 0.01) but HRV parameters HRV standard deviation (HRV-SD) (166.0 +/- 33.2 vs. 138.2 +/- 38.7; p < 0.04), HRV-SD1 (78.8 +/- 11.7 vs. 63.2 +/- 36.5; p < 0.01), and HRV-SD2 (220.6 +/- 48.0 vs. 183.8 +/- 45.8; p < 0.05) were increased. In the group of competitive athletes studied, some evidence of mild insomnia was found but objectively measured sleep structure did not differ from those of healthy controls. The TST, with a mean of 6.8 h in both the LS and the GK group, is lower than the sleep duration recommended by the professional societies American Academy of Sleep Medicine (AASM), Sleep Research Society (SRS), and National Sleep Foundation (NSF) for young adults. In contrast, cardiac autonomic regulation during sleep was significantly better in group LS than in the group GK and is in agreement with findings from 24-hour Holter ECG studies. The development of objective, mobile, and non-obtrusive measurement methods simplifies the assessment of sleep structure and concomitant characteristic autonomic parameters and therefore could be increasingly used in personalized health and performance management in competitive athletes.

Objective: This study evaluates correlations between insomnia and mental health during the COVID-19 pandemic in Germany.

Methods: The internet-based International COVID-19 Sleep Study (ICOSS) questionnaire including sociodemographic questions as well as sleep- and emotion-related scales was distributed in Germany during the COVID-19 pandemic from May 1 to September 30, 2020. Insomnia and mental state were assessed using the Insomnia Severity Index (ISI), Patient Health Questionnaire (PHQ), Generalized Anxiety Disorder (GAD-2), and visual analogue scale. Qualitative analyses of demographic characteristics were performed and correlation analyses of the variables calculated.

Results: A total of 1103 individuals participated and 858 valid questionnaires (70.61% females) were obtained. Mean age and body mass index were 41.97 +/- 12.9 years and 26 +/- 5.9 kg/m(2), respectively. Most participants were married (n = 486, 56.6%), living in the city (n = 646, 75.3%), and white (n = 442, 51.5%). The prevalence of insomnia, anxiety, and depression was 19.5% (ISI > 7), 6.6% (GAD-2 > 3), and 4.8% (PHQ-2 > 3), respectively. Compared to the insomnia group, the mean and median ISI, PHQ-4, PHQ-2, and GAD-2 scores of the non-insomnia group were lower, while their mean and median quality of life and quality of health scores were significantly higher (P < 0.05). Pearson correlation analysis showed a positive correlation between the ISI and PHQ-2 (r = 0.521, P < 0.001), GAD-2 (r = 0.483, P < 0.001), and PHQ-4 scores (r = 0.562, P < 0.001); however, the ISI score negatively correlated with the quality of life (r = -0.490, P < 0.001) and quality of health scores (r = -0.437, P < 0.001). Conclusion Insomnia, anxiety, and depression were very prevalent during the pandemic. Anxiety and depression were more severe in the insomnia than in the non-insomnia group, and insomnia and mental health are closely related.

Purpose: Despite polysomnography being the gold standard method of diagnosing obstructive sleep apnea (OSA), it is time-consuming and has long waiting lists. Alternative methods including questionnaires and portable sleep devices have been developed to increase the speed of diagnosis. However, most questionnaires such as the STOP-BANG questionnaire (SBQ) are limited due to low specificity. This study evaluated the value of SBQ to screen for OSA and compared it with the oxygen desaturation index (ODI) and their combination.

Methods: This retrospective study included patients who completed the SBQ and underwent a night at the sleep lab or home sleep testing. The ODI was extracted from these sleep study reports. The combination of SBQ with ODI and their individual scores were compared with apnea-hypopnea index (AHI) in terms of their accuracy in diagnosing OSA. Sensitivity, specificity, and area under the curve (AUC) for different severities of OSA were calculated and compared.

Results: Among 132 patients, SBQ showed a sensitivity of 0.9 and a specificity of 0.3 to screen for OSA. As the severity of OSA increased, the sensitivity increased whilst specificity decreased for both measurements. ODI achieved an increased specificity of 0.8 and could correctly diagnose OSA 86% of the time which was better than SBQ's 60%. For all severities of OSA, ODI alone displayed a larger AUC than SBQ and similar AUC to their combination.

Conclusion: ODI produced a higher specificity and AUC than SBQ. Furthermore, ODI combined with SBQ failed to increase diagnostic value. Therefore, ODI may be the preferred way to initially screen patients for OSA as an easy-to-use alternative compared to SBQ.

Objective: Central sleep apnea (CSA) is associated with increased morbidity and mortality in patients with heart failure (HF). We aimed to explore the effectiveness of phrenic nerve stimulation (PNS) on CSA in patients with HF.

Methods: This was a prospective and non-randomized study. The stimulation lead was inserted into the right brachiocephalic vein and attached to a proprietary neurostimulator. Monitoring was conducted during the implantation process, and all individuals underwent two-night polysomnography.

Results: A total of nine subjects with HF and CSA were enrolled in our center. There was a significant decrease in the apnea-hypopnea index (41 +/- 18 vs 29 +/- 25, p = 0.02) and an increase in mean arterial oxygen saturation (SaO2) (93% +/- 1% vs 95% +/- 2%, p = 0.03) after PNS treatment. We did not observe any significant differences of oxygen desaturation index (ODI) and SaO2 < 90% (T90) following PNS. Unilateral phrenic nerve stimulation might also categorically improve the severity of sleep apnea.

Conclusion: In our non-randomized study, PNS may serve as a therapeutic approach for CSA in patients with HF.

Objective: This study aimed to evaluate the effect of sacubitril-valsartan (SV) on central apneas (CA) and obstructive apneas (OA) in patients with heart failure with reduced ejection fraction (HFrEF).

Methods: In patients with HFrEF, SV initiation was titrated to the highest tolerable dosage. Patients were evaluated with portable apnea monitoring, echocardiography, and cardiopulmonary exercise testing at baseline and 3 months later.

Results: Of a total of 18 patients, 9 (50%) had OA, 7 (39%) had CA, and 2 (11%) had normal breathing. SV therapy was related to a reduction in NT-pro BNP and an improvement in LV function after 3 months. Portable apnea monitoring revealed a significant decrease of the respiratory event index (REI) after treatment with SV (20 +/- 23 events/h to 7 +/- 7 events/h, p = 0.003). When subgrouping according to type of apneas, REI, and time spent below 90% saturation (T90) decreased in patients with CA and OA (all p < 0.05).

Conclusion: In this prospective study, SV treatment for 3 months in patients with CA and OA is associated with a significant decrease in REI.

In 2009, the Assessment of SpondyloArthritis international Society (ASAS) published a definition of 'active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis'. This new definition of an 'ASAS-positive MRI' was integral to new classification criteria for axial spondyloarthritis that were published in the same year. The ASAS MRI definition had the considerable advantage of simplicity and the definition gained popularity as guidance for interpreting MRI of the sacroiliac joints in clinical practice. However, classification criteria are not designed for use in clinical practice with the consequence that overreliance on the presence of bone marrow edema, which is the principal determinant of an 'ASAS-positive MRI', may result in a tendency to overcall inflammatory sacroiliitis in the clinical setting. This article aims to inform the reader about the rationale behind the ASAS definition of a positive MRI and ASAS classification criteria, their proper use in research and why they should not be used in clinical practice. The article also contains guidance for an updated imaging protocol and interpretation of images including typical imaging findings, differential diagnosis, and common pitfalls.

Background: The insufficient quality of external post-mortem examination of the corpse as well as the documentation of death certificates (DCs) have long been the subject of controversial discussions in the literature. Frequently criticized are faulty or implausible causal chains and a falsely attested natural mode of death.

Objective: It was investigated which type of death was attested by the responsible physician in the case of an unknown or inexactly determined cause of death and how often an autopsy at the institute for forensic medicine was carried out in these cases.

Method: The confidential and non-confidential parts of all DCs in the second quarter of 2013 of the city of Munich were screened in a standardized manner and statistically analyzed.

Results: The study comprised a total of 3228 DCs. Out of all cases, 900 DCs (27.9%) were classified under Ia and 462 cases (14.3%) under Ic as an unknown or inexactly determined cause of death. Despite being certified as an unknown cause of death, 4,0% of these cases were assigned a natural death. Autopsies were performed far more often for cases with unknown cause of death (Ia: 52.0% and Ic: 52.1%, respectively) than in cases with an inexactly determined cause of death (Ia: 5.2% and Ic: 7.5%, respectively).

Discussion: In most cases, the responsible physician attested the correct manner of death in the case of an unknown cause of death (96.0%) but in 4.0% they also falsely certified a natural manner of death at the same time. This has far-reaching consequences, especially in terms of criminal proceedings, since if a natural death is reported, the investigating authorities are not notified with the aim of clarifying the circumstances of the death. At this point, there is a risk of a recording gap for non-natural deaths.

Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) frequently contributes to failure of systemic therapy. While the radiosensitizing properties of 5-fluorouracil (FU) are well known, it is unknown whether ionizing radiation (IR) sensitizes towards FU cytotoxicity. Here, we hypothesize that upregulation of thymidine phosphorylase (TP) by IR reverses FU chemoresistance in PDAC cells. The FU resistant variant of the human PDAC cell line AsPC-1 (FU-R) was used to determine the sensitizing effects of IR. Proliferation rates of FU sensitive parental (FU-S) and FU-R cells were determined by WST-1 assays after low (0.05 Gy) and intermediate dose (2.0 Gy) IR followed by FU treatment. TP protein expression in PDAC cells before and after IR was assessed by Western blot. To analyze the specificity of the FU sensitizing effect, TP was ablated by siRNA. FU-R cells showed a 2.7-fold increase of the half maximal inhibitory concentration, compared to FU-S parental cells. Further, FU-R cells showed a concomitant IR resistance towards both doses applied. When challenging both cell lines with FU after IR, FU-R cells had lower proliferation rates than FU-S cells, suggesting a reversal of chemoresistance by IR. This FU sensitizing effect was abolished when TP was blocked by anti-TP siRNA before IR. An increase of TP protein expression was seen after both IR doses. Our results suggest a TP dependent reversal of FU-chemoresistance in PDAC cells that is triggered by IR. Thus, induction of TP expression by low dose IR may be a therapeutic approach to potentially overcome FU chemoresistance in PDAC.

Purpose: Patient-Reported Outcomes (PROs) and its measures (PROMs) are key to outcome assessment in Fibromyalgia (FM) trials. The aim of this review was to investigate which domains and instruments were assessed in recent FM trials and to compare them to recommendations by the Outcome Measures in Rheumatology (OMERACT) initiative. In addition, we investigated the overlap with a generic health assessment approach, i.e. eight domains suggested by the Patient-Reported Outcome Measurement Information System (R) (PROMIS (R)).

Methods: In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature search in scientific databases including PubMed, PsycInfo, and Embase was conducted to identify studies that assessed at least two dimensions of health-related quality of life (HRQoL) from 2015 to June 2022. Non-randomized and randomized controlled trials were included in the analysis. We extracted PROs and PROMs used in each study.

Results: From 1845 identified records, 107 records out of 105 studies met the inclusion criteria. Studies investigated 50 PROs using 126 different PROMs. Most frequently assessed domains were pain, depression, fatigue, and anxiety (> 95% of the studies). The disease-specific FIQ was the most frequently applied PROM (82%). Overall, only 9% of the studies covered all domains deemed mandatory by OMERACT. Very few studies covered all eight generic health domains suggested by PROMIS.

Conclusion: The majority of trials covered most OMERACT domains or generic PROMIS health domains. There was, however, great variability in the instruments used to assess the domains, which points at a limited degree of standardization in the field.

Rationale: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system.

Objectives: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg.

Methods: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2).

Results: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group.

Conclusions: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen.

Purpose: Loneliness among the elderly is a widespread phenomenon and is connected to various negative health outcomes. Nevertheless, loneliness among elderly inpatients, especially those with a psychiatric diagnosis, has hardly been examined. Our study assessed loneliness in elderly inpatients, identified predictors, and compared levels of loneliness between inpatients on psychiatric and somatic wards.

Methods: N = 100 elderly inpatients of a somatic and psychiatric ward were included. Levels of loneliness were assessed, as were potential predictors such as depression, psychological resilience, severity of mental illness, well-being, daily functioning, and psychiatric diagnosis. Analyses of group differences and hierarchical multiple regression analysis were conducted.

Results: 37% of all inpatients reported elevated levels of loneliness. Significant predictor variables were self-reported depressive symptoms, well-being, severity of mental illness, being single and living with a caregiver. Hierarchical multiple regression analysis revealed that the full model explained 58% of variance in loneliness. Psychiatric inpatients' loneliness was significantly higher than loneliness in somatic inpatients. When analyzing group differences between inpatients with different main psychiatric diagnoses, highest levels were found in patients with an affective disorder, followed by those treated for organic mental disorder. Since the study took place during the COVID-19 pandemic, potential influence of different measurement points (lockdown vs. no lockdown) were analyzed: Differences in loneliness depending on the phase of the pandemic were non-significant.

Conclusion: Elderly inpatients experience high levels of loneliness, especially those with a mental disorder. Interventions to reduce loneliness in this population should address predictors of loneliness, preferably through multiprofessional interventions.

Background: Magnetic resonance imaging (MRI) is used to detect the prostate index lesion before targeted biopsy. However, the number of biopsy cores that should be obtained from the index lesion is unclear. The aim of this study is to analyze how many MRI-targeted biopsy cores are needed to establish the most relevant histopathologic diagnosis of the index lesion and to build a prediction model.

Methods: We retrospectively included 451 patients who underwent 10-core systematic prostate biopsy and MRI-targeted biopsy with sampling of at least three cores from the index lesion. A total of 1587 biopsy cores were analyzed. The core sampling sequence was recorded, and the first biopsy core detecting the most relevant histopathologic diagnosis was identified. In a subgroup of 261 patients in whom exactly three MRI-targeted biopsy cores were obtained from the index lesion, we generated a prediction model. A nonparametric Bayes classifier was trained using the PI-RADS score, prostate-specific antigen (PSA) density, lesion size, zone, and location as covariates.

Results: The most relevant histopathologic diagnosis of the index lesion was detected by the first biopsy core in 331 cases (73%), by the second in 66 cases (15%), and by the third in 39 cases (9%), by the fourth in 13 cases (3%), and by the fifth in two cases (<1%). The Bayes classifier correctly predicted which biopsy core yielded the most relevant histopathologic diagnosis in 79% of the subjects. PI-RADS score, PSA density, lesion size, zone, and location did not independently influence the prediction model.

Conclusion: The most relevant histopathologic diagnosis of the index lesion was made on the basis of three MRI-targeted biopsy cores in 97% of patients. Our classifier can help in predicting the first MRI-targeted biopsy core revealing the most relevant histopathologic diagnosis; however, at least three MRI-targeted biopsy cores should be obtained regardless of the preinterventionally assessed covariates.

Background: The coronavirus disease 2019 (COVID-19) pandemic has underscored the importance of real world data in everyday clinical practice and has highlighted some long-standing problems of our healthcare system such as gaps in primary data collection, hurdles in the evaluation of patient data, and complexity regarding the data exchange between different institutions. In addition, changes in physician-patient relationships such as transitions from a paternalistic to a partnership-based relationship model as well as increasing digitalization have shaped our modern understanding of healthcare, emphasizing the issue of patient autonomy and self-efficacy and highlighting the need for innovative, patient-centered approaches.

Methods: Using the patient journey as a theoretical construct, we describe the collection of different types of real world data, their meaning and handling.

Conclusion: Mapping the patient journey process combined with a widely used data standard can lead to the acquisition of primary data in the healthcare sector which can be used by all medical treatment institutions. This will lead to an exchange of valuable data between institutions and circuit the current problem of proprietary formats. Furthermore, the evaluation of patient-reported outcomes as a standard in the clinical routine could enhance patients' autonomy and optimize treatment. Thus, the overall treatment effectiveness and survival of patients can be improved by creating a common data language and using a holistic, human-centered care approach through integrating perspectives of patients and their loved ones.

The concept of solvent drag, i.e., water and solutes sharing the same pore and their transport being frictionally coupled, was first proposed in the early 1950s. During the following decades, it was applied to transport processes across cell membranes as well as transport along the paracellular pathway. Water-driven solute transport was proposed as the major mechanism for electrolyte and nutrient absorption in the small intestine and for Cl- and HCO3- reabsorption in the renal proximal tubule. With the discovery of aquaporins as transcellular route for water transport and the claudin protein family as the major determinant of paracellular transport properties, new mechanistic insights in transepithelial water and solute transport are emerging and call for a reassessment of the solvent drag concept. Current knowledge does not provide a molecular basis for relevant solvent drag-driven, paracellular nutrient, and inorganic anion (re-)absorption. For inorganic cation transport, in contrast, solvent drag along claudin-2-formed paracellular channels appears feasible.

Introduction: A TCS after primary closure of meningomyeloceles is a known complication of the spina bifida disease. Data on the outcome after SSCU surgery is heterogeneous and lacking standardization. Thus we aimed to find a reliable system for assessment of the bladder function before and after SSCU surgery and document postoperative outcome.

Methods: A retrospective study was performed on a cohort of patients with spina bifida diagnosis. In total, 130 patients underwent 182 SSCU surgeries, 56 of those met our inclusion criteria. A classification system, including two different methods, was used. The AC system used baseline pressure and detrusor over activity to define three levels of bladder dysfunction, the second method ranked the severity of bladder dysfunction by awarding points from 0 to 2 for bladder capacity, maximal detrusor pressure during autonomous contractions, leak point pressure and vesicoureteral reflux A high score is correlated with a severe bladder dysfunction.

Results: Gender distribution was equally (male: n = 29; 51.8%; female: n = 27; 48.2%). The median age at SSCU was 902 years (range 0.5-22.8 years). After SSCU, the stage improved in 11 patients (19.6%), worsened in 11 (19.6%) patients and remained the same in 34 patients (60.7%) after intervention (AC score). Non-worsening was observed in a total of 45 cases (80.4%) (p < 0.001). MHS score (n = 27, 48.2%) improved, remained unchanged (n = 12, 21.4%), 17 patients worsened (30.4%). Non-worsening in postoperative bladder functional outcome was demonstrated in 39 cases (69.6%) over all (p < 0.005). Regardless of whether bladder function is categorized by AC or MHS, postoperative outcome worsened significantly when SSCU was performed due to increasing deterioration in motor function alone (p < 0.05). Of the 24 cases with NOD as indication, 22 (91.7%) had an unchanged (n = 10; 41.7%) or improved (n = 12; 50.0%), meaning positive neuro-orthopedic outcome, only 2 (8.3%) deteriorated (p < 0.001).

Conclusion: Our study presents reliable evaluation systems for bladder function in spina bifida patients. Since indications for SSCU surgery differ, it is important to know the possible effects on bladder function after this surgical procedure. Even a mild impairment of bladder function has a risk to deteriorate after SSCU surgery. Particularly interesting becomes this with regard to the fact that the prevalence of TCS might become more frequent with the rising numbers of prenatal closures of meningomyeloceles.

Introduction: To assess the long-term effect of bladder augmentation surgery in patients with spina bifida and to identify risk factors for severe bladder dysfunction requiring bladder augmentation.

Methods: A retrospective analysis was performed on 178 patients with spina bifida, 23 of them underwent bladder augmentation. Surgery outcome was evaluated according to urodynamic assessments at three follow-up time points per patient up to 120 months postoperatively. The results were compared to the preoperative situation and to the non-operated control group. Bladder function was evaluated using the modified Hostility score. To identify risk factors for bladder dysfunction requiring bladder augmentation, characteristics such as type of spina bifida, lesion level and therapy of bladder dysfunction were analyzed.

Results: A high spinal lesion level is a risk factor for requiring bladder augmentation. In the BA group, significantly more thoracic lesions were found than NBA group, BA: 26.1%, NBA: 8.4% (p = 0.021). With bladder augmentation surgery, the modified Hostility score decreased from a preoperative median value of 4.3 +/- 1.4 to 1.6 +/- 1.0 at the third postoperative follow-up (FU3 = 61-120 months after surgery). In the reference group, the score of the last urological assessment was 2.0 +/- 1.5. The age at which clean intermittent catheterization or anticholinergic medication started had no significant influence on the decision to perform bladder augmentation.

Discussion/conclusion: Spina bifida patients with bladder augmentation had a significant improvement of the bladder function even at long-term follow-up. A high level of spinal lesion was a predisposing factor for requiring a bladder augmentation.

Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of beta-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-beta-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-beta-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.

INTRODUCTION

Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels.

METHOD

Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview.

RESULTS

We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6-24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode.

CONCLUSIONS

Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.