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Background: Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC). Methods: The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity. Findings: On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84–1.29], p = 0.711 and HR 1.18 [0.95–1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79–1.17], p = 0.67 and HR 1.48 [1.16–1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02–1.74], p = 0.037) and OS (HR 1.26 [1.03–1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3–3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62–3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55–5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02–1.37], p = 0.031) but not OS (HR 1.05 [0.91–1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used. Interpretation: In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international collaborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit. Funding:Cambridge Hepatopancreatobiliary Department Research Fund.

Background: Thiazide diuretics are a mainstay in the management of hypertension and often associated with dyselectrolytemias. We investigated the prevalence of and risk factors for hyponatremia and hypokalemia in thiazide users, substance-specific differences, and the association of thiazides with syncope and falls. Methods: In this cross-sectional analysis all patients admitted to an interdisciplinary emergency department in Switzerland between January 1, 2017, and December 31, 2018, with measurements of serum sodium and potassium were included. Data regarding serum electrolytes and creatinine were analyzed to classify for dysnatremias, dyskalemias, and acute kidney injury. Chart reviews were performed to screen for syncope or falls. Results: A total of 1604 patients (7.9%) took thiazides. Acute kidney injury was significantly more common in thiazide users (22.1 vs 7%, P < .0001). Hyponatremia (22.1 vs 9.8%, P < .0001) and hypokalemia (19 vs 11%, P < .0001) were more frequent with thiazides. Thiazide use together with higher age and female sex were independent predictors of hyponatremia and hypokalemia. A dose-dependent effect was found for electrolyte disorders, and there was a variance in risk between the investigated substances with chlorthalidone bearing the highest and hydrochlorothiazide the lowest risk. Patients taking thiazide diuretics had significantly more episodes of syncope and falls. Conclusions: Thiazide use is a clear risk factor for hyponatremia and hypokalemia. The effect appears to be dose-dependent and highly variable depending on the substance. Syncope and falls seem to be causally related to thiazide use. Especially in patients who are elderly, female, and prone to falls, the use of thiazide diuretics should be thoroughly questioned.

Purpose We aimed to investigate the prevalence, risk factors and outcome of hypo- and hypernatremia in emergency patients with acute kidney injury (AKI). Methods In this cross-sectional analysis all emergency patients between January 1st 2017 and December 31st 2018 with measurements of creatinine and sodium were included. Baseline characteristics, medication and laboratory data were gathered. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract baseline creatinine. For all other patients the ADQI backformula was used to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of dysnatremias and outcome. Results AKI was found in 8% of patients. 392 patients (23.16%) had hyponatremia, 24 (1.4%) had hypernatremia. Use of potassium sparing diuretics, a medical cause for emergency referral, use of thiazide diuretics and AKI stage were the strongest risk factors for hyponatremia. Loop diuretics, a medical cause for emergency referral and AKI stage were risk factors for hypernatremia. In patients with all classes of hyponatremia, length of hospital stay was significantly longer compared to patients with a normal serum sodium. In the binary logistic regression analysis with death as outcome, hyponatremia as well as severe hypernatremia were independent risk factors for mortality. Conclusions Dysnatremias are common in emergency patients with AKI. Diuretic medication is a major risk factor for hypo- and hypernatremia. Both hyponatremia and severe hypernatremia were independent risk factors for adverse outcome.

Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006–2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33–80). The median follow-up was 21.7 months (range 0.3–92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P 0.05). Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Die neurologisch-psychiatrische Schlafmedizin umfasst die Diagnostik der Insomnien, Hypersomnien und Parasomnien. Ziel der Arbeit war die Uberprufung, welche Aufnahmediagnosen zu welchen Entlassdiagnosen fuhren und wie haufig ein Diagnosewechsel erfolgt. Hierzu wurden die polysomnografischen Befunde aller neurologisch-schlafmedizinischen Patienten im SRH Krankenhaus Pfullendorf der Jahre 2010 bis 2017 analysiert. In einem standardisierten diagnostischen Verfahren wurden Patienten mit neurologisch/psychiatrisch-schlafmedizinischen Fragestellungen untersucht. Im stationaren Setting wurden zwei Tagestests (Multipler Wachbleibetest und Multipler Schlaflatenztest) in drei Polysomnografien eingebettet. An der Studie nahmen 401 Patienten in 414 stationaren Aufenthalten teil. Die neurologisch-schlafmedizinische Diagnostik fuhrte in 46,9 % der Falle zu einem Diagnosewechsel. Haufigste Entlassdiagnose war bei 229 Patienten die Insomnie. Bei 44 Patienten wurde die Entlassdiagnose Narkolepsie gestellt. Die neurologisch/psychiatrisch-schlafmedizinische Diagnostik erlaubt die klare Diagnosestellung und damit den Beginn adaquater Therapie.

The presented work illustrates the synthesis of a nonlinear model-based observer for the longitudinal dynamics estimation of a wheelset. This approach offers some significant improvements, such as an enhanced adherence to prescribed brake distances and an advanced usability of the condition-based maintenance of brake systems. The investigation of a single wheelset in a test rig environment enables, for example, the usage of an extended set of sensors to reliably validate the observers. The presented observer design process covers three main steps: identification of the characteristic system disturbances, implementation of the nonlinear observer dynamics, and parametrization of the observer via multicase optimization. With regard to the longitudinal dynamics, the variations of the friction conditions in the wheel–rail interface and in the interface between brake pads and brake disc have a crucial influence. Therefore, a parameter estimator and a disturbance observer are implemented, since these methods allow for a specific consideration of these disturbances. The obtained results prove that the observers accurately estimate the system behavior and provide reliable information on the longitudinal dynamics.

CTLA4Ig has been shown to improve kidney allograft function, but an increased frequency of early rejection episodes poses a major obstacle for more widespread clinical use. The deleterious effect of CTLA4Ig on Treg numbers provides a possible explanation for graft injury. Therefore, we aimed at improving CTLA4Ig's efficacy by therapeutically increasing the number of Tregs. Murine cardiac allograft transplantation (BALB/c to B6) was performed under CTLA4Ig therapy modeled after the clinically approved dosing regimen and Tregs were transferred early or late after transplant. Neither early nor late Treg transfer prolonged allograft survival. Transferred Tregs were traceable in various lymphoid compartments but only modestly increased overall Treg numbers. Next, we augmented Treg numbers in vivo by means of IL2 complexes. A short course of IL2/anti-IL2-complexes administered before transplantation reversed the CTLA4Ig-mediated decline in Tregs. Of note, the addition of IL2/anti-IL2-complexes to CTLA4Ig therapy substantially prolonged heart allograft survival and significantly improved graft histology on day 100. The depletion of Tregs abrogated this effect and resulted in a significantly diminished allograft survival. The increase in Treg numbers upon IL2 treatment was associated with a decreased expression of B7 on dendritic cells. These results demonstrate that therapy with IL2 complexes improves the efficacy of CTLA4Ig by counterbalancing its unfavorable effect on Tregs.

The “Next Generation Train” (NGT) is a double-deck high speed train concept in light-weight design that has been established as a technical and project framework in which the German Aerospace Center gathers its long-term railway vehicle research. To reduce wheel and rail wear and to enhance the passenger capacity, a mechatronic running gear with independently rotating wheels (IRW) is a key vehicle component under research. This running gear requires an advanced control of the lateral dynamics in order to fully exploit its potential in minimizing wear and noise, but this relies on information on its lateral position relative to the track. In daily railway operation it is difficult to directly measure this displacement of the wheel-pair. However, according to previous work it is possible to design an appropriate observer to estimate the lateral position, but its estimation accuracy highly depends on the chosen sensor configuration. Nevertheless, it was shown that the lateral dynamics of the running were not completely reproduced by the system description especially at suddenly changing directions in the movement of the IRW. In this work the system description is complemented by a nonlinear description of the wheel–rail geometry. Therefore, an observability analysis and an observer synthesis to estimate the lateral position for the nonlinear system of the 1:5 scaled hardware running gear is carried out. For validation purposes an extended Kalman filter with the U-D formalism is implemented at the real-time environment of the testbed and the estimation accuracy of the observer configurations is compared.

Hypervitaminosis D is a rare reason for hypercalcemia and associated with acute kidney injury. We report on two cases of hypercalcemia and acute kidney injury because of vitamin D intoxication successfully treated with denosumab. Case 1 is an 83-year-old woman, who was initially treated for 2 weeks with intravenous hydration, steroids and thereafter with furosemide without any effect on serum calcium levels and renal function. Because acute renal failure discouraged us to use intravenous bisphosphonate therapy, we applicated 60 mg denusomab subcutaneously. This led to a prompt reduction in serum calcium levels and improvement of renal function within 1 week. Case 2 is a 45-year-old athletic woman, who refused the standard therapy of steroids and forced diuresis for vitamin D intoxication. After 1 day of rehydration therapy, she received 60 mg denusomab. Similar to case 1 serum calcium declined and renal function improved within 7 days.

This chapter analyzes the transitions to adulthood of young university graduates in Morocco, more precisely, activists of the unemployed graduates movement. Their protests offer a case in point to shed light on how youth transitions in the region are institutionalized and brokered. Based on particpant observation and life story interviews, this chapter applies a ‘youth transitions regime’ perspective in order to highlight he political dimension of youth transitions. How is the structure of these transitions and the hegemonic cultural definitions of ‘youth’ and ‘adulthood’ implicit in them linked to class, gender, social exclusion and precariousness? Has the ‘Arab Spring’ impacted the Moroccan youth transitions regime and the strategies of the unemployed graduates?

Background No data concerning the prevalence and risk factors of dyskalemia in acute kidney injury (AKI) exist. We investigated (a) prevalence rates, (b) risk factors and (c) outcome of hypo- and hyperkalemia in emergency patients. Methods In this cross-sectional analysis, all patients admitted to the emergency department of a large public hospital in Switzerland between January 1st 2017 and December 31st 2018 with measurements of creatinine and potassium were included. Baseline characteristics, medication and laboratory data were extracted. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract their baseline creatinine. For all other patients, the ADQI backformula was used in order to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of hyperkalemia and outcome. Results AKI was found in 8% of patients. Hyperkalemia was present in 13% and hypokalemia in 11% of patients with AKI. AKI stage, potassium-sparing diuretics, ACE inhibitors and underlying CKD were the strongest risk factors for hyperkalemia. Hyperkalemia as well as profound hypokalemia were independently associated with prolonged length of stay and in-hospital mortality. The study is limited by its dependency on chart review data in order to identify patients with chronic kidney disease and by limitations of the ADQI backformula to calculate baseline creatinine. Conclusions Dyskalemias are common in emergency patients with AKI and are independent risk factors for adverse outcomes. Potassium-sparing diuretics, ACE-inhibitors, AKIN stage and CKD are predictors of hyperkalemia in AKI.

Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear.Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern.Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P 0.05).Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Background The value of liver resection (LR) for metachronous pancreatic ductal adenocarcinoma (PDAC) metastases remains controversial. However, in light of increasing safety of liver resections, surgery might be a valuable option for metastasized PDAC in selected patients. Methods We performed a retrospective, multicenter study including patients undergoing hepatectomy for metachronous PDAC liver metastases between 2004 and 2015 to analyze postoperative outcome and overall survival. All patients were operated with curative intent. Patients with oligometastatic metachronous liver metastasis with definitive chemotherapy (n = 8) served as controls. Results Overall 25 patients in seven centers were included in this study. The median age at the time of LR was 63.8 years (56.9–69.9) and the median number of metastases in the liver was 1 (IQR 1–2). There were eight non-anatomical resections (32%), 15 anatomical minor (60%) and 2 major LR (8%). Postoperative complications occurred in eleven patients (eight Clavien-Dindo grade I complications (32%) and three grade IIIa complications (12%), respectively). The 30-day mortality was 0%. The median length of stay was 8.6 days (IQR 5–11). Median overall survival following LR was 36.8 months compared to 9.2 months in patients with metachronous liver metastasis with chemotherapy (p = 0007). Discussion Liver resection for metachronous PDAC metastasis is safe and feasible in selected patients. To address general applicability and to find factors for patient selection, larger trials are urgently warranted.

Background The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. Material and methods To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 μg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. Results N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. Conclusion This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.

In the field of longitudinal train dynamics the brake process is not only a safety critical aspect but it also determines the capacity of the rail network. Therefore, a reduction of the brake distance increases the safety level and the network capacity at the same time. However, to implement an advanced brake control set-up, the knowledge of the wheel-rail adhesion and the brake pad-disc friction is usually necessary. Since the direct measurement of these determining parameters is not reasonable due to technical and economic reasons, the present work presents an estimator framework for their online identification. To ensure a robust and reliable performance of the estimator, a generic wagon model is designed and the observability of the nonlinear system is evaluated. Furthermore, a reasonable synthesis of an extended Kalman filter is discussed that takes account of the system characteristics. In the end, the test results from a roller rig verify the accurate and robust performance of the developed estimator and confirm the great potential of such a concept in the context of mechatronic railway systems.

State observer design turned out to be crucial in several recent railway vehicles projects on active control and condition monitoring at DLR, but may also be useful for emerging technologies like the cyber physical system and the digital twin approach or the realization of predictive maintenance concepts. With this background and motivation the paper presents a process in three steps: (i) an initial analysis results in a physical model, (ii) the subsequent transfer to state space representation facilitates the prove of observability and (iii) the observer synthesis supports the design of the observer feedback law. Results from two projects, one related to longitudinal or traction dynamics, the other associated to the guidance task of independently rotating wheels, demonstrate the application of the observer design process and offers a comparison of observer estimates with measurements.