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BackgroundExecutive functions (EF) consolidate during adolescence and are impaired in various emerging psychiatric disorders, such as pediatric Major Depressive Disorder (pMDD) and Borderline Personality Disorder. Previous studies point to a marked heterogeneity of deficits in EF in pMDD. We examined the hypothesis that deficits in EF in adolescents with pMDD might be related to comorbid Borderline Personality features (BPF).MethodsWe examined a sample of 144 adolescents (15.86 ± 1.32) diagnosed with pMDD. Parents rated their child’s EF in everyday life with the Behavior Rating Inventory of Executive Function (BRIEF) and BPF with the Impulsivity and Emotion Dysregulation Scale (IED-27). The adolescents completed equivalent self-rating measures. Self- and parent-ratings of the BRIEF scores were compared with paired t-Tests. Correlation and parallel mediation analyses, ICC, and multiple regression analyses were used to assess symptom overlap, parent-child agreement, and the influence of depression severity.ResultsOver the whole sample, none of the self- or parent-rated BRIEF scales reached a mean score above T > 65, which would indicate clinically impaired functioning. Adolescents tended to report higher impairment in EF than their parents. Depression severity was the strongest predictor for BPF scores, with Emotional Control predicting parent-rated BPF and Inhibit predicting self-rated BPF. Furthermore, the Behavioral Regulation Index, which includes EF closely related to behavioral control, significantly mediated the relationship between depression severity and IED-27 factors emotional dysregulation and relationship difficulties but not non-suicidal self-injuries.ConclusionOn average, adolescents with depression show only subtle deficits in executive functioning. However, increased EF deficits are associated with the occurrence of comorbid borderline personality features, contributing to a more severe overall psychopathology. Therefore, training of executive functioning might have a positive effect on psychosocial functioning in severely depressed adolescents, as it might also improve comorbid BPF.Clinical trial registrationwww.ClinicalTrials.gov, identifier NCT03167307.

Abstract Background The demographic changes towards ageing of the populations in developed countries impose a challenge to trauma centres, as geriatric trauma patients require specific diagnostic and therapeutic procedures. This study investigated whether the integration of new standard operating procedures (SOPs) for the resuscitation room (ER) has an impact on the clinical course in geriatric patients. The new SOPs were designed for severely injured adult trauma patients, based on the Advanced Trauma Life Support (ATLS) and imply early whole-body computed tomography (CT), damage control surgery, and the use of goal-directed coagulation management. Methods Single-centre cohort study. We included all patients ≥65 years of age with an Injury Severity Score (ISS) ≥ 9 who were admitted to our hospital primarily via ER. A historic cohort was compared to a cohort after the implementation of the new SOPs. Results We enrolled 311 patients who met the inclusion criteria between 2000 and 2006 (group PreSOP) and 2010–2012 (group SOP). There was a significant reduction in the mortality rate after the implementation of the new SOPs (P = .001). This benefit was seen only for severely injured patients (ISS ≥ 16), but not for moderately injured patients (ISS 9–15). There were no differences with regard to infection rates or rate of palliative care. Conclusions We found an association between implementation of new ER SOPs, and a lower mortality rate in severely injured geriatric trauma patients, whereas moderately injured patients did not obtain the same benefit. Trial registration Clinicaltrials.gov NCT03319381, retrospectively registered 24 October 2017.

Abstract Background While mainly larger hospitals have introduced routine anti-Xa assays for rivaroxaban (RXA), these are not readily available to smaller hospitals often relying on routine coagulation tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT). The aim of our study was to investigate the effect of RXA plasma concentration on the standard coagulation tests PT (Quick test and INR) and aPTT in a large group of real-life patients. We further assessed whether normal results of these standard coagulation assays are sufficient to exclude surgically relevant RXA plasma concentration, defined as > 50 mcg/l. Methods This retrospective study included all patients between 2012 and 2016 where anti-Xa (calibrated for RXA), PT (Quick test and INR), and/or aPTT were determined from the same sample. PT is expressed as Quick value (% of normal plasma pool). In total, 1027 measurements in 622 patients were eligible for analysis: 752 measurements of 505 patients for Quick/INR and 594 measurements of 417 patients for aPTT. Results A moderate correlation of PT/Quick (Pearson's correlation coefficient − 0.59; p < 0.001), INR (Pearson's correlation coefficient 0.5; p < 0.001), and aPTT (Pearson's correlation coefficient 0.53; p < 0.001) with RXA plasma concentration was observed. However, in 50% of all samples with a normal PT/Quick, in 25% of all samples with a normal INR and in 80% of all samples with a normal aPTT residual RXA plasma concentration was surgically relevant. Conclusion Although a moderate correlation of RXA plasma concentration with PT/Quick, INR, and aPTT was observed, standard coagulation assays are not sufficient to exclude surgically relevant RXA plasma concentrations.

Abstract Background Electrosurgery is fundamental to the precise, fast and bloodless preparation of internal thoracic artery grafts in cardiac surgery. The PEAK PlasmaBlade is a monopolar electrosurgical device that uses pulsed radiofrequency energy to generate a plasma-mediated discharge along an insulated electrode, creating a cutting edge while the blade stays near body temperature. The aim of this study is to compare the histological samples, cardiac computed-tomography of graft patency, and clinical outcomes of patients after off-pump coronary artery bypass grafting with preparation of the internal thoracic arteries by a conventional electrosurgical device and the PlasmaBlade. Methods In twenty subjects one internal thoracic artery was prepared with PlasmaBlade and the other artery with a conventional electrosurgical device. Histological samples were evaluated for three factors for potential graft failure: endothelial damage, integrity of the vessel wall and adventitial hemorrhage. Five samples per artery were evaluated by a novel scoring method based on the exposed circumference of the histological sample (“0”: 0%, “1”: 1–25%, “2”: 26–50%, “3”: 51–75%, “4”: ≥76% of the circumference). The Wilcoxon signed ranks test for mean scores within subjects was performed. Six-month-follow up by cardiac computed tomography for evaluation of graft patency was completed in 16 patients. Results Histological results demonstrated significantly less endothelial damage after PlasmaBlade (83% vs 60%, absolute: 75/90 vs. 53/89 samples with score “0–1”, p = 0.04). PlasmaBlade samples demonstrated a tendency to better wall integrity (72% vs. 54%, absolute: 64/89 vs. 47/87 samples with score “0–1”, p = 0.32). There were no differences in endothelial bleeding (PlasmaBlade 46% vs. electrosurgery 53%, absolute: 41/88 vs. 48/90 samples with score “0–1”, p = 0.63). Computed tomography confirmed non-inferiority of the PlasmaBlade to conventional electrosurgery with a patency rate of 94%. Conclusion Histologically, internal thoracic arteries harvested with PlasmaBlade demonstrate a more intact endothelial layer and a tendency to better wall integrity. Computed tomography of graft patency speaks for non-inferiority to conventional electrosurgery. PlasmaBlade may be preferable to conventional electrosurgery, if further follow-up confirms patency of internal thoracic arteries. Trial registration NCT03510026, registered 4th April 2018 (retrospectively registered).

Abstract Background In sepsis, early outcome prediction would allow investigation of both adaptive mechanisms underlying survival and maladaptive mechanisms resulting in death. The aim of this study was to test whether early changes in heart rate monitored by telemetry could predict outcome in a long-term rat model of fecal peritonitis. Methods Male Wistar rats (n = 24) were instrumented with a central venous line for administration of fluids, antibiotics and analgesics. A telemetry transmitter continuously collected electrocardiogram signals. Sepsis was induced by intraperitoneal injection of fecal slurry, and the animals were observed for 48 h. Additional animals underwent arterial cannulation at baseline (n = 9), 4 h (n = 16), or 24 h (n = 6) for physiology and laboratory measurements. Results 48-h mortality was 33% (8/24), with all deaths occurring between 4 and 22 h. Septic animals were characterized by lethargy, fever, tachycardia, positive blood cultures, and elevated cytokine (IL-1, IL-6, TNF alpha) levels. An increase in heart rate ≥ 50 bpm during the first 4 h of sepsis predicted death with sensitivity and specificity of 88% (p = 0.001). Conclusions In this long-term rat sepsis model, prognostication could be made early by telemetry-monitored changes in heart rate. This model enables the study of underlying mechanisms and the assessment of any differential effects of novel therapies in predicted survivors or non-survivors.

Purpose This study aims to objectively characterize the effect of successful nerve sparing (NS) during radical prostatectomy (RP) on postoperative urinary continence (UC) using International Index of Erectile Function (IIEF)-scores and a previously described Expanded Prostate Cancer Index Composite (EPIC) score cutoff value (COV) for UC. Several notable studies on this topic present conflicting outcomes. This is largely due to a lack of clear definitions and consensus regarding preserved erectile function (EF) and UC. Methods This study is comprised of all patients who underwent RP at the Kantonsspital Baden, Switzerland, between 2004 and 2013. Patients completed self-assessment questionnaires for UC (EPIC) and EF (IIEF) pre- and postoperatively (3, 6, 9, 12, 18, and 24 months; yearly thereafter). We used a previously described EPIC subscore COV, with “satisfactory continence” signified by a score >85. Statistical analysis was performed using Kaplan-Meier and Cox regression analyses for “surgeon-” and “IIEF-defined” NS definitions. Results Of 236 men with a median age of 63 years (interquartile range [IQR], 59–66 years) and median follow-up time of 48 months (IQR, 30–78 months), 176 underwent unilateral (n=33) or bilateral (n=143) NS RP. Fifty-four underwent non-NS (NNS) RP. Kaplan-Meier analyses identified the following risk factors for UC: age, prostate volume, cancer risk group, and NS status. In surgeon-defined NS RP cases, multivariate analysis for regaining continence demonstrated no significant difference (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.48–1.25; P=0.3). With successful IIEF-defined NS RPs, regression analysis demonstrated no significant difference (HR, 0.89; 95% CI, 0.59–1.35; P=0.58). Conclusions In our population, analysis and comparison of surgeon- and IIEF-defined NS and NNS cohorts revealed that NS RP did not improve postoperative UC. The conservation of UC alone should not motivate surgeons or patients to pursue NS RP.

Abstract Background Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10-80%. Delirium was first described more than half a century ago in the cardiac surgery population, where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population. This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies. Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100β will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery. Methods/design The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo. Discussion There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium. Trial registration ClinicalTrials.gov, NCT02433041. Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015.

Abstract Background At the University Hospital Zurich (USZ) and the Cantonal Hospital of Lucerne (LUKS) an individualized goal-directed coagulation and transfusion algorithm was introduced and implemented before 2012 (Coagulation algorithm of the USZ: USZ-Alg; of the LUKS: LUKS-Alg). Main differences between both algorithms are: 1) A target haematocrit-range of 0.21–0.24 (USZ-Alg) vs. a lower haematocrit limit only (LUKS-Alg). 2) Blind coagulation-package in selected cases (LUKS-Alg only). 3) Factor XIII substitution is considered earlier according to the USZ-Alg. The Aim of this study was to analyse the impact of two different coagulation algorithms on the administration of allogeneic blood products, coagulation factors, the frequency of point of care measurements and haemoglobin level during resuscitation in trauma patients. Methods This retrospective, multicentre, observational study included all adult trauma patients with an injury severity score (ISS) ≥ 16 primarily admitted to the USZ or the LUKS in the period of 2012 to 2014. Referred patients and patients with missing/incomplete records of the initial treatment at the emergency department (ED) were excluded. Two propensity score matched groups were created using a non-parsimonious logistic regression to account for potential differences in patient and trauma epidemiology. Results A total of 632 patients meeting the inclusion criteria were admitted to the two hospitals: 428 to the USZ and 204 to the LUKS. Two Propensity score matched groups (n = 172 per group) were created. Treatment with USZ-Alg compared with LUKS-Alg resulted in a lower number of patients receiving RBC transfusion (11.6% vs. 29.7%, OR 3.2, 95% CI 1.8–5.7, p

Abstract Background Biliary tract cancer (BTC) is a dismal disease, even after curative intent surgery. We conducted this prospective, non-randomized phase II study to evaluate the feasibility and efficacy of cisplatin and gemcitabine as adjuvant treatment in patients with resected BTC. Methods Patients initially received gemcitabine 1000 mg/m2 alone on days 1, 8 and 15 every 28-days for a total of six cycles (single agent cohort), and after protocol amendment a combination therapy with gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 was administered every 21 days for a total of eight cycles (combined regimen cohort). Treatment was planned to start within eight weeks after curative intent resection. Adverse events, disease-free survival and overall survival were assessed. Results Overall 30 patients were enrolled in the study from August 2008 and last patient was enrolled at 2nd December 2014. The follow-up of the patients ended at 31st December 2016. The first 9 patients received single-agent gemcitabine. The interim analysis met the predefined feasibility criteria and, from September 2010 on, the second group of 21 patients received the combination of cisplatin plus gemcitabine. In the single-agent cohort with gemcitabine the median relative dose intensity (RDI) was 100% (IQR 88.3–100). Patients treated with the combination cisplatin-gemcitabine received an overall median RDI of 100% (IQR 50–100) for cisplatin and 100% (IQR 75–100) for gemcitabine respectively. The most significant non-hematological adverse events (grade 3 or 4) were fatigue (20%), infections during neutropenia (10%), and two cases of biliary sepsis (7%). Abnormal liver function was seen in 10% of the patients. One patient died due to infectious complications during treatment with cisplatin and gemcitabine. The median disease-free survival (DFS) was 14.9 months (95% CI 0–33.8) with a corresponding 3-year DFS of 43.1 ± 9.1%. The median overall survival (OS) was 40.6 months (95% CI 18.8–62.3) with a 3-year OS of 55.7 ± 9.2%. No statistically significant differences in survival were seen between the two treatment cohorts. Conclusion Adjuvant chemotherapy with gemcitabine with or without cisplatin was well tolerated and resulted in promising survival of the patients. Trial registration The study was retrospectively registered on 25th June 2009 at clinicaltrials.gov ( NCT01073839 ).

Purpose To determine an objective cutoff value (COV) for urinary incontinence (UI) using the Expanded Prostate Cancer Composite (EPIC) score after radical prostatectomy (RP). Methods From 2004–2013, all RP patients at our institution completed the EPIC urinary domain (EPIC-UD) questionnaire preoperatively and 6 weeks; 3, 6, 9, 12, and 18 months postoperatively; and yearly thereafter. The EPIC-UD is composed of several questions, 4 of which address UI qualitatively (EPIC-UI). Furthermore, patients were asked to complete a global quality of life (QoL) questionnaire regarding continence. The EPIC COV was calculated using receiver operating characteristic (ROC) analysis. Correlations between the EPIC-UI and quantitative QoL were evaluated using the Kendall-Tau test. Results We analyzed 239 patients with a median age of 63 years (interquartile range [IQR], 59–66 years), a median follow-up of 48 months (IQR, 30–78 months) and a median preoperative EPIC-UI score of 100 (IQR, 91.75–100). The ROC analysis for the distinction between EPIC-UI and the use of ≤1 pad/day yielded an EPIC-UI COV of >85, which we termed the UI-85, with an area under the curve of 0.857 (P

Abstract Background Menstrually related migraine (MRM) in the hormone-free interval (HFI) of combined hormonal contraceptives (CHC) are according to the ICHD definition also estrogen withdrawal migraines (EWH). MRMs are less responsive to acute medication. Therefore short-term prevention, initiated 1–2 days before onset of the anticipated bleeding and continued for 6 days, is recommended. Such a long prophylactic triptan use might increase the risk for medication overuse headache in women suffering in addition from non-menstrual migraines. In CHC users onset of hormone decline is predictable. It is however unknown, whether the EWHs are rather associated with onset of hormone withdrawal or onset of bleeding. Improved understanding of this relation might contribute to better define and shorten the time interval for prevention. Methods For this observational diary-based pilot study we collected data from daily conducted headache diaries of CHC users with MRM in at least two of three cycles, visiting our clinic from 2009 to 2015. We analyzed frequency of migraines for each hormone free day, onset of migraine, onset of bleeding and the relation of migraine to onset of bleeding in the 7-day period following estrogen withdrawal. We identified in addition the onset of migraine attacks lasting more than 1 day (episodes). Results Forty patient charts met the inclusion criteria, what allowed us to analyze 103 cycles. The mean number of migraine days in the HFI was 2.2 ± 1.6. Migraine started typically on days 1–5 and bleeding on days 3–5. In relation to first day of bleeding, migraines started on days −1 to 4. Almost half of the migraine attacks lasted longer than 24 h, despite the use of rescue medication. Conclusion MRM in CHC users starts on bleeding days −1 to 4, what differs from findings in the natural cycle. Referring to the HFI interval migraine started mostly on days 1–5. According to these data, it seems to be reasonable to initiate short-term prevention at the last day of pill use or the first day of the HFI and continue for 5 days.

Abstract Background Sepsis research relies on animal models to investigate the mechanisms of the dysregulated host response to infection. Animal welfare concerns request the use of potent analgesics for the Refinement of existing sepsis models, according to the 3Rs principle. Nevertheless, adequate analgesia is often missing, partly because the effects of analgesics in this particular condition are unknown. We evaluated the use of nalbuphine, an opioid with kappa agonistic and mu antagonistic effects, in rats with and without experimental sepsis. Methods Male Wistar rats were anesthetized with isoflurane and instrumented with a venous line for drug administration. Arterial cannulation allowed for blood pressure measurements and blood sampling in short-term experiments of non-septic animals. Nalbuphine (or placebo) was administered intravenously at a dose of 1 mg/kg/h. Long-term (48 h) experiments in awake septic animals included repetitive clinical scoring with the Rat Grimace Scale and continuous heart rate monitoring by telemetry. Sepsis was induced by intraperitoneal injection of faecal slurry. Nalbuphine plasma levels were measured by liquid chromatography—high resolution mass spectrometry. Results In anesthetized healthy animals, nalbuphine led to a significant reduction of respiratory rate, heart rate, and mean arterial pressure during short-term experiments. In awake septic animals, a continuous nalbuphine infusion did not affect heart rate but significantly improved the values of the Rat Grimace Scale. Nalbuphine plasma concentrations remained stable between 4 and 24 h of continuous infusion in septic rats. Conclusions In anaesthetised rats, nalbuphine depresses respiratory rate, heart rate, and blood pressure. In awake animals, nalbuphine analgesia improves animal welfare during sepsis.

Background Clinical characteristics and outcomes of takotsubo syndrome (TTS) patients with malignancy have not been fully elucidated. This study sought to explore differences in clinical characteristics and to investigate short‐ and long‐term outcomes in TTS patients with or without malignancy. Methods and Results TTS patients were enrolled from the International Takotsubo Registry. The TTS cohort was divided into patients with and without malignancy to investigate differences in clinical characteristics and to assess short‐ and long‐term mortality. A subanalysis was performed comparing long‐term mortality between a subset of TTS patients with or without malignancy and acute coronary syndrome (ACS) patients with or without malignancy. Malignancy was observed in 16.6% of 1604 TTS patients. Patients with malignancy were older and more likely to have physical triggers, but less likely to have emotional triggers compared with those without malignancy. Long‐term mortality was higher in patients with malignancy (P

Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.

BACKGROUND Providing efficient healthcare is important for hospitals. Shorter and longer length of hospital stay (LOS) outliers influence financial results and reimbursement. The objective of this study was to identify independent diagnosis related group (DRG)-related risk factors for shorter and longer LOS outlier status. METHODS A retrospective case-control study was conducted at a Swiss level 1 trauma centre between January 2012 and December 2014. The study included all patients with available information on LOS based on DRG. Many predictor variables were tested. The outcome variable was the DRG-based LOS. Logistic regression models were fitted for shorter and longer LOS outliers, with a significance level of

BACKGROUND The introduction of direct acting antivirals (DAAs) for the therapy of chronic hepatitis C (CHC) has revolutionised treatment and marks a paradigm shift in the approach to this disease, rendering interferon-based therapies obsolete. AIMS OF THE STUDY We retrospectively and prospectively evaluated treatment results after the introduction of DAA in Switzerland in a cohort of patients with CHC. METHODS We examined 565 patients who received DAA treatment for CHC between November 2013 and June 2016 with regard to HCV genotype, fibrosis stadium, treatment and outcome. In addition, outcome of re-treatment and resistance-associated substitutions (RAS) in patients that did not achieve sustained virological response (SVR) were evaluated. The majority of patients participate in the Swiss Hepatitis C Cohort Study. Data were evaluated in an intention-to-treat and a modified intention-to-treat analysis. RESULTS Overall SVR rate for all patients was 94% (530 of 565, 95% CI 92–96%). Of 350 patients with HCV genotype 1 CHC, 335 achieved SVR, resulting in an SVR rate of 96% (335 of 350, 95% CI 94–98%). Patients with HCV genotype 2 achieved SVR in 94% (48 of 51, 95% CI 87–100%). Patients with HCV genotype 3 showed SVR of 92% (98 of 107, 95% CI 87–97%). In patients with HCV genotype 4, the SVR rate was substantially lower at 85% (49 of 57, 95% CI 76–94%). The rate of advanced liver fibrosis (Metavir F3/F4) assessed by means of liver biopsy or Fibroscan® in the entire patient population was 71% (404 of 565). Out of 35 patients that did not achieve SVR after DAA treatment, 32 had a relapse and 3 patients showed viral breakthrough. In 17 of 35 cases (49%) patients were treatment naïve and 21 of 35 patients (60%) were cirrhotic. RAS genotyping of HCV was performed in 14 patients. Nine of these 14 patients (60%) carried mutations in the NS5A region of the virus genome. Twenty-seven percent of patients who experienced treatment failure were not treated with recommended regimens as a result of drug availability and reimbursement limitations. CONCLUSION In Switzerland, novel DAA treatments for CHC reflect the positive results from registration trials. Genotypes 2 and 4 remained more difficult to treat between 2014 and 2016. Patients who experienced a relapse after DAA treatment in Switzerland predominantly showed mutations in the NS5A region of the virus genome. DAA treatment limitations in Switzerland did prevent optimal treatment regimens in some patients.

The ability to characterize the mechanical properties of erythrocytes is important in clinical and research contexts: to diagnose and monitor hematologic disorders, as well as to optimize the design of cardiovascular implants and blood circulating devices with respect to blood damage. However, investigation of red blood cell (RBC) properties generally involves preparatory and processing steps. Even though these impose mechanical stresses on cells, little is known about their impact on the final measurement results. In this study, we investigated the effect of centrifuging, vortexing, pipetting, and high pressures on several markers of mechanical blood damage and RBC membrane properties. Using human venous blood, we analyzed erythrocyte damage by measuring free hemoglobin, phosphatidylserine exposure by flow cytometry, RBC deformability by ektacytometry and the parameters of a complete blood count. We observed increased levels of free hemoglobin for all tested procedures. The release of hemoglobin into plasma depended significantly on the level of stress. Elevated pressures and centrifuging also altered mean cell volume (MCV) and mean corpuscular hemoglobin (MCH), suggesting changes in erythrocyte population, and membrane properties. Our results show that the effects of blood handling can significantly influence erythrocyte damage metrics. Careful quantification of this influence as well as other unwanted secondary effects should thus be included in experimental protocols and accounted for in clinical laboratories.

BACKGROUND Based on a reduction in morbidity and mortality, cardiac resynchronisation therapy (CRT) has evolved as a standard therapy for patients with advanced heart failure. OBJECTIVE To provide insight into patient demographics, safety, echocardiographic remodelling and long-term follow-up of patients treated with CRT in a “real-world” setting at a Swiss tertiary care centre. METHODS Patients implanted with a CRT device at the University Heart Centre Zurich between 2000 and 2015 were consecutively enrolled. Initial clinical and echocardiographic therapy response as well as long-term follow-up for mortality (defined as all-cause death, heart transplantation or ventricular assist device implantation) and hospitalisation for heart failure were assessed. RESULTS A total of 418 patients with a median age of 66 years at the time of CRT implantation (78% male) were enrolled. Serious peri-interventional complications (from the time of implantation up to 14 days thereafter) were rare and included systemic infections in 2.4%, pneumothorax in 3.3% and haematoma requiring revision in 2.2% of cases. Overall, the Kaplan-Meier estimate for 5-year freedom from the composite endpoint (hospitalisation for heart failure or mortality) was 55.8%; the Kaplan-Meier estimate for 5-year freedom from mortality was 64.1%. CRT was associated with a significant symptomatic improvement and left ventricular reverse remodelling. ​ Overall, 3.9% of patients did not respond to cardiac resynchronisation therapy (decline in left ventricular ejection fraction [LVEF] >5%), whereas 35.1% experienced neither a continued decline nor a relevant improvement of LVEF (±5%). In the remaining 61% of patients we observed an improvement in LVEF of more than 5%. Forty percent and 31% of patients were super responders, defined as an absolute LVEF improvement of ≥10% and by a relative reduction of left ventricular end-diastolic volume index by 20% or more. Super-response to CRT was associated with a significant benefit in terms of survival and rehospitalisation rates. CONCLUSION Our data are consistent with large multicentre trials and indicate that CRT is similarly effective in a real-world setting in Switzerland.

To investigate the feasibility and accuracy of texture analysis to distinguish through objective and quantitative image information between healthy and infarcted myocardium with computed tomography (CT).Twenty patients (5 females; mean age 56±10years) with proven acute myocardial infarction (MI) and 20 patients (8 females; mean age 42±15years) with no cardiac abnormalities (hereafter termed controls) underwent contrast-enhanced cardiac CT. Short axis CT images of the left ventricle (LV) were reconstructed at the slice thicknesses 1mm, 2mm, and 5mm. Two independent, blinded readers segmented the LV in controls and patients. Texture analysis was performed yielding first-level features based on the histogram (variance, skewness, kurtosis, entropy), second-level features based on the gray-level co-occurrence matrix (GLCM) (contrast, correlation, energy and homogeneity), and third-level features based on the gray-level run-length matrix (GLRLM).Inter-and intrareader agreement was good to excellent for all histogram (intraclass correlation coefficient (ICC):0.70-0.93) and for all GLCM features (ICC:0.66-0.99), and was variable for the GLRLM features (ICC:-0.12-0.99). Univariate analysis showed significant differences between patients and controls for 2/4 histogram features, 3/4 GLCM and for 6/11 GLRLM features and all assessed slice thicknesses (all,p

[This corrects the article DOI: 10.1371/journal.pone.0167214.].

QUESTIONS: Treatment of patients with severe injuries is costly, with best results achieved in specialised care centres. However, diagnosis-related group (DRG)-based prospective payment systems have difficulties in depicting treatment costs for specialised care. We analysed reimbursement of care for severe trauma in the first 3 years after the introduction of the Swiss DRG reimbursement system (2012–2014). MATERIAL/METHODS: The study included all patients with solely basic insurance, hospital admission after 01.01.2011 and discharge in 2011 or 2012, who were admitted to the resuscitation room of the University Hospital of Zurich, aged ≥16 years and with an injury severity score (ISS) ≥16 (n = 364). Clinical, financial and administrative data were extracted from the electronic medical records. All cases were grouped into DRGs according to different SwissDRG versions. We considered results to be significant if p ≤0.002. RESULTS: The mean deficit decreased from 12 065 CHF under SwissDRG 1.0 (2012) to 2 902 CHF under SwissDRG 3.0 (2014). The main reason for the reduction of average deficits was a refinement of the DRG algorithm with a regrouping of 23 cases with an ISS ≥16 from MDC 01 to DRGs within MDC21A. Predictors of an increased total loss per case could be identified: for example, high total number of surgical interventions, surgeries on multiple anatomical regions or operations on the pelvis (p ≤0.002). Psychiatric diagnoses in general were also significant predictors of deficit per case (p

BACKGROUND:Brain metastasis is a common endpoint in patients suffering from malignant melanoma. However, little is known about factors that predispose to brain metastases. OBJECTIVE:We performed a retrospective clinical and pathological investigation of melanoma patients with brain metastases in order to better characterise this patient population. METHODS:193 melanoma patients with brain metastasis histologically diagnosed between 1990 and 2015 at the University Hospital Zurich were retrospectively identified and further specified for sex, age at diagnosis and detection of brain metastasis, and localisation. In addition, data were extracted regarding the subtype of primary melanoma, Breslow tumour thickness, Clark Level, mutation status, extent of metastatic spread and history of a second melanoma. RESULTS:We found a significant male predominance (n = 126/193; 65%; p < 0.001). Breslow tumour thickness showed a wide range from 0.2 to 12.0 mm (n = 99; median 2.3 mm). 14 of 101 melanomas (14%) were classified as T1, thereof 11 (79%) were found in men. In 32 of 193 patients (17%), the primary melanoma was unknown. CONCLUSIONS:Of special interest in our series is the high incidence of male predominance (79%) in cases of thin metastasing melanoma (14%), implicating genetic or epigenetic (hormonal) gender differences underlying tumour progression. Additionally, the high percentage of unknown primary melanoma (17%), at least partly representing completely regressed melanomas, indicates the importance of immune surveillance in melanoma progression.

To evaluate the performance of low contrast media (CM) dose dual-energy computed tomography pulmonary angiography (CTPA) with advanced monoenergetic reconstructions in patients with suspected pulmonary embolism (PE).The study had institutional review board approval; all patients gave written informed consent. Forty-one patients (25 men, 16 women, mean age 62.9±14.7 years) undergoing low CM dose (15ml, 6g iodine) dual-energy CTPA with advanced monoenergetic reconstructions were matched via propensity-scoring based on logistic regression analysis with a comparison group of 41 patients (24 men, 17 women, mean age 62.7±13.9 years) undergoing standard CM dose single-energy CTPA (80ml, 24g iodine). Subjective (noise, artifacts) and objective (attenuation, noise, contrast-to-noise ratio (CNR)) image quality was assessed by two blinded, independent readers. All patients underwent clinical follow-up after three months for evaluation of adverse events.Interrater agreement for subjective image quality in both groups ranged from fair to excellent (ICC: 0.46-0.84); agreement for objective image quality was excellent (ICC: 0.83-0.93). There was no significant difference regarding subjective noise (p = 0.15-0.72) and artifacts (p = 0.16-1) between the low and the standard CM dose group. There was no significant difference regarding CNR between the CM dose groups (p = 0.11-0.87). Seven of the 41 (17%) patients in the low and 5/41 (12%) in the standard CM dose group were diagnosed with PE (p = 0.32). No patient suffered from subsequent PE or PE-associated death during the follow-up period.Dual-energy CTPA with advanced monoenergetic reconstruction is feasible with 6g iodine and allows for the diagnosis and safe exclusion of central, lobar, and segmental PE.

BACKGROUND:Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. METHODS:The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1-4 infection, including 88 patients with available IL28b genotyping. RESULTS:Mean ribavirin levels varied between 0.68-5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. CONCLUSION:While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon.

Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS).Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression.A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23-89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact was detected for tumor size (p = 0.02), nodal status (p8 (p12) and DFS (p = 0.01).In early BC patients, tumors with high HER2 amplification ratios (>8), may less likely respond to standard trastuzumab-containing therapies. Although, we obtained a similar effect for high HER2 gene copy numbers, this provides only an indirect speculation and not a proof that high HER2/CEP17 ratios may induce HER2 resistance.

PRINCIPLES: Reimbursement systems have difficulties depicting the actual cost of burn treatment, leaving care providers with a significant financial burden. Our aim was to establish a simple and accurate reimbursement model compatible with prospective payment systems. METHODS: A total of 370 966 electronic medical records of patients discharged in 2012 to 2013 from Swiss university hospitals were reviewed. A total of 828 cases of burns including 109 cases of severe burns were retained. Costs, revenues and earnings for severe and nonsevere burns were analysed and a linear regression model predicting total inpatient treatment costs was established. RESULTS: The median total costs per case for severe burns was tenfold higher than for nonsevere burns (179 949 CHF [167 353 EUR] vs 11 312 CHF [10 520 EUR], interquartile ranges 96 782–328 618 CHF vs 4 874–27 783 CHF, p

PrinciplesCase weights of Diagnosis Related Groups (DRGs) are determined by the average cost of cases from a previous billing period. However, a significant amount of cases are largely over- or underfunded. We therefore decided to analyze earning outliers of our hospital as to search for predictors enabling a better grouping under SwissDRG.Methods28,893 inpatient cases without additional private insurance discharged from our hospital in 2012 were included in our analysis. Outliers were defined by the interquartile range method. Predictors for deficit and profit outliers were determined with logistic regressions. Predictors were shortlisted with the LASSO regularized logistic regression method and compared to results of Random forest analysis. 10 of these parameters were selected for quantile regression analysis as to quantify their impact on earnings.ResultsPsychiatric diagnosis and admission as an emergency case were significant predictors for higher deficit with negative regression coefficients for all analyzed quantiles (pConclusionWe suggest considering psychiatric diagnosis, admission as an emergency case and admission from an external health care provider as DRG split criteria as they predict large, consistent and significant losses.

OBJECTIVES: The short-term results of subclavian artery cannulation (SC) for acute type-A dissection repair have been reported to be superior in regard to mortality and neurological outcomes when compared to femoral cannulation (FC). This study evaluates the long-term results of subclavian artery cannulation versus femoral cannulation for repair of acute type-A dissection with particular regard to neurological deficits, mortality and the need for re-operations. METHODS: From 1992–2005, 346 patients underwent surgical repair of acute type-A dissection of which 290 patients survived the operation. SC was performed in 114 patients and FC in 176 patients. Follow-up (FU) was completed in 89.5% (n = 259) and the medium FU-period was 42 months (SC) and 69 months (FC). Endpoints were persistence of neurological-deficits, mortality, major complications and necessity for re-operations. RESULTS: Overall survival and disease-free survival at 5 years were significantly higher in the SC group (83% vs. 71%; p = 0.022 and 74% vs. 61%; p = 0.044). Freedom of re-operation also appeared to be higher in the SC group (89% vs. 79%; p = 0.125). During the follow-up period, 28 patients (11/114 vs. 17/176; p = 0.58) suffered from neurological deficits of which 16 patients had permanent neurological-deficits at the 5 year follow-up. Of these patients, significantly more belonged to the FC group indicating an improved neurological-outcome for the SC group (3/11 vs. 13/17; p = 0.019). CONCLUSIONS: This study demonstrates excellent long-term outcomes after emergency surgery for acute type-A dissection. Subclavian artery perfusion represents an excellent approach to repair acute type-A dissection. Beside a significantly reduced long-term mortality, this technique provides an improved neurological outcome and a higher disease-free survival-rate.

PURPOSE: Chronic hand and wrist pain is a common clinical issue for orthopaedic surgeons and rheumatologists. The purpose of this study was 1. To analyze the interobserver agreement of SPECT/CT, MRI, CT, bone scan and plain radiographs in patients with non-specific pain of the hand and wrist, and 2. to assess the diagnostic accuracy of these imaging methods in this selected patient population. MATERIALS AND METHODS: Thirty-two consecutive patients with non-specific pain of the hand or wrist were evaluated retrospectively. All patients had been imaged by plain radiographs, planar early-phase imaging (bone scan), late-phase imaging (SPECT/CT including bone scan and CT), and MRI. Two experienced and two inexperienced readers analyzed the images with a standardized read-out protocol. Reading criteria were lesion detection and localisation, type and etiology of the underlying pathology. Diagnostic accuracy and interobserver agreement were determined for all readers and imaging modalities. RESULTS: The most accurate modality for experienced readers was SPECT/CT (accuracy 77%), followed by MRI (56%). The best performing, though little accurate modality for inexperienced readers was also SPECT/CT (44%), followed by MRI and bone scan (38% each). The interobserver agreement of experienced readers was generally high in SPECT/CT concerning lesion detection (kappa 0.93, MRI 0.72), localisation (kappa 0.91, MRI 0.75) and etiology (kappa 0.85, MRI 0.74), while MRI yielded better results on typification of lesions (kappa 0.75, SPECT/CT 0.69). There was poor agreement between experienced and inexperienced readers in SPECT/CT and MRI. CONCLUSIONS: SPECT/CT proved to be the most helpful imaging modality in patients with non-specific wrist pain. The method was found reliable, providing high interobserver agreement, being outperformed by MRI only concerning the typification of lesions. We believe it is beneficial to integrate SPECT/CT into the diagnostic imaging algorithm of chronic wrist pain.

The objective of this work is to quantify age-related differences in the characteristics and coupling of cerebral arterial inflow and cerebrospinal fluid (CSF) dynamics. To this end, 3T phase-contrast magnetic resonance imaging blood and CSF flow data of eleven young (24 ± 3 years) and eleven elderly subjects (70 ± 5 years) with a comparable sex-ratio were acquired. Flow waveforms and their frequency composition, transfer functions from blood to CSF flows and cross-correlations were analyzed. The magnitudes of the frequency components of CSF flow in the aqueduct differ significantly between the two age groups, as do the frequency components of the cervical spinal CSF and the arterial flows. The males' aqueductal CSF stroke volumes and average flow rates are significantly higher than those of the females. Transfer functions and cross-correlations between arterial blood and CSF flow reveal significant age-dependence of phase-shift between these, as do the waveforms of arterial blood, as well as cervical-spinal and aqueductal CSF flows. These findings accentuate the need for age- and sex-matched control groups for the evaluation of cerebral pathologies such as hydrocephalus.

Recent molecular studies provide evidence for a significant transcriptional plasticity of tumor cell subpopulations that facilitate an active contribution to tumor vasculature. This feature is accompanied by morphological changes both in vitro and in vivo. Herein, we investigated the morphological plasticity of tumor cells with special focus on vasculogenic mimicry and neovascularisation in human melanoma and mouse xenografts of human melanoma cell lines. In melanoma xenograft experiments, different vessel markers and green fluorescent protein expression were used to show how melanoma cells contribute to neovascularization. Additionally, we analyzed neovascularization in 49 primary melanomas and 175 melanoma metastases using immunostaining for blood (CD34) and lymphatic (D2-40) vessel-specific markers. We found significantly more lymphatic vessels in primary melanomas than in melanoma metastases (p