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ISTerre is part of Labex OSUG@2020. Use of the Geochem- istry–Mineralogy platform at ISTerre is acknowledged. The authors wish to aknowledge the ESRF for provision of beam time (MA4498). We are also thankful to Dr Pierre-Olivier Autran for useful insights on tomographic reconstructions and Dr Marta Majkut for discussions on grain orientation calcu- lations. The authors also thank Dr Irina Snigireva and Dr Nathaniel Findling for SEM characterization of the samples and Dr Catherine Dejoie for complementary high-resolution powder diffraction data from the ID22 beamline of the ESRF., The mechanism of hydration of calcium sulfate hemihydrate (CaSO4 0.5H2O) to form gypsum (CaSO4 2H2O) was studied by combining scanning 3D X-ray diffraction (s3DXRD) and phase contrast tomography (PCT) to determine in situ the spatial and crystallographic relationship between these two phases. From s3DXRD measurements, the crystallographic structure, orientation and position of the crystalline grains in the sample during the hydration reaction were obtained, while the PCT reconstructions allowed visualization of the 3D shapes of the crystals during the reaction. This multi-scale study unfolds structural and morphological evidence of the dissolution–precipitation process of the gypsum plaster system, providing insights into the reactivity of specific crystallographic facets of the hemihydrate. In this work, epitaxial growth of gypsum crystals on the hemihydrate grains was not observed.

Background: For logistical reasons, some high-volume centers have developed surgical programs wherein 1 surgical team performs 2 pancreatoduodenectomies on a single day. It is unclear whether this practice has a negative impact on surgical outcome. Methods: We conuducted a retrospective analysis including all consecutive open pancreatoduodenectomies in a single high-volume center (2014–2021). Pancreatoduodenectomies were grouped as the first (pancreatoduodenectomy-1) or second (pancreatoduodenectomy-2) pancreatoduodenectomy on a single day (ie, paired pancreatoduodenectomies) and as pancreatoduodenectomy-3 whenever 1 pancreatoduodenectomy was performed per day (ie, unpaired). Patients undergoing minimally invasive procedures were excluded. The primary outcomes were major morbidity (ie, Clavien-Dindo grade ≥IIIa) and mortality. Results: Among 689 patients, 151 patients had undergone minimally invasive pancreatoduodenectomy, leaving 538 patients after open pancreatoduodenectomy for inclusion. The overall rate of major morbidity was 37.4% (n = 200/538) and in-hospital/30-day mortality 1.7% (n = 9/538). Overall, 136 (25.3%) patients were operated in 68 pancreatoduodenectomy-1/ pancreatoduodenectomy-2 pairs and 402 (74.7%) patients as unpaired pancreatoduodenectomy (pancreatoduodenectomy-3). No differences were found between pancreatoduodenectomy-1 and pancreatoduodenectomy-2 regarding the rates of major morbidity (35.3% vs 26.5%; P = .265) and mortality (1.5% vs 0%; P = .999). Between the 68 pancreatoduodenectomy-1/ pancreatoduodenectomy-2 pairs and the 402 unpaired pancreatoduodenectomies, the rates of major morbidity (30.9% vs 39.6%; P = .071) and mortality (0.7% vs 2.0%; P = .461) did not differ significantly. In multivariable logistic regression analysis, pancreatoduodenectomy-1 was not associated with major morbidity (odds ratio = 0.913 [95% confidence interval 0.515–1.620]; P = .756), whereas pancreatoduodenectomy-2 was associated with less major morbidity (odds ratio = 0.522 [95% confidence interval 0.277–0.983]; P = .045). Conclusion: In a high-volume setting, performing 2 consecutive open pancreatoduodenectomies on a single operating day appears to be safe. This approach may be an option when logistically required.

Background: Follow-up in patients with intraductal papillary mucinous neoplasm (IPMN) aims to detect advanced neoplasia (high-grade dysplasia/cancer) in an early stage. The 2015 American Gastroenterological Association (AGA), 2017 International Association of Pancreatology (IAP), and the 2018 European Study Group on Cystic tumours of the Pancreas (European) guidelines differ in their recommendations on indications for surgery. However, it remains unclear which guideline is most accurate in predicting advanced neoplasia in IPMN. Methods: Patients who underwent surgery were extracted from a prospective database (January 2006–January 2021). In patients with IPMN, final pathology was compared with the indication for surgery according to the guidelines. ROC-curves were calculated to determine the diagnostic accuracy for each guideline. Results: Overall, 247 patients underwent surgery for cystic lesions. In 145 patients with IPMN, 52 had advanced neoplasia, of which the AGA guideline would have advised surgery in 14 (27%), the IAP and European guideline in 49 (94%) and 50 (96%). In 93 patients without advanced neoplasia, the AGA, IAP, and European guidelines would incorrectly have advised surgery in 8 (8.6%), 77 (83%) and 71 (76%). Conclusion: The European and IAP guidelines are clearly superior in detecting advanced neoplasia in IPMN as compared to the AGA, albeit at the cost of a higher rate of unnecessary surgery. To harmonize care and to avoid confusion caused by conflicting statements, a global evidence-based guideline for PCN in collaboration with the various guidelines groups is required once the current guidelines require an update.

Automation of Managed Pressure Drilling (MPD) allows for fast and accurate pressure control in drilling operations. The achievable performance in automated MPD with model-based controllers is determined by the controller and, indirectly, also by the hydraulics model used for controller synthesis. On the one hand, such a hydraulics model should accurately capture essential flow dynamics of the system such as, e.g., wave propagation effects, for which typically complex models are needed. On the other hand, a suitable model should be simple enough to facilitate high-performance controller design as well as to support fast simulation studies supporting well scenario analysis. This paper shows that low-order models in terms of delay differential equations can effectively meet these requirements. Moreover, we propose a data-based model reduction technique to construct these low-order delay models. Next, based on this reduced-complexity model, a novel controller is designed to regulate the downhole pressure. Simulation results confirm that this controller outperforms existing pressure controllers in realistic drilling scenarios related to the mitigation of liquid kicks and mud losses encountered when drilling into high- or low-pressure zones.

Background: Several registries focus on patients undergoing minimally invasive liver surgery (MILS). This study compared transatlantic registries focusing on the variables collected and differences in baseline characteristics, indications, and treatment in patients undergoing MILS. Furthermore, key variables were identified. Methods: The five registries for liver surgery from North America (ACS-NSQIP), Italy, Norway, the Netherlands, and Europe were compared. A set of key variables were established by consensus expert opinion and compared between the registries. Anonymized data of all MILS procedures were collected (January 2014–December 2019). To summarize differences for all patient characteristics, treatment, and outcome, the relative and absolute largest differences (RLD, ALD) between the smallest and largest outcome per variable among the registries are presented. Results: In total, 13,571 patients after MILS were included. Both 30- and 90-day mortality after MILS were below 1.1% in all registries. The largest differences in baseline characteristics were seen in ASA grade 3–4 (RLD 3.0, ALD 46.1%) and the presence of liver cirrhosis (RLD 6.4, ALD 21.2%). The largest difference in treatment was the use of neoadjuvant chemotherapy (RLD 4.3, ALD 20.6%). The number of variables collected per registry varied from 28 to 303. From the 46 key variables, 34 were missing in at least one of the registries. Conclusion: Despite considerable variation in baseline characteristics, indications, and treatment of patients undergoing MILS in the five transatlantic registries, overall mortality after MILS was consistently below 1.1%. The registries should be harmonized to facilitate future collaborative research on MILS for which the identified 46 key variables will be instrumental.

This paper proposes a data-driven model reduction approach on the basis of noisy data with a known noise model. Firstly, the concept of data reduction is introduced. In particular, we show that the set of reduced-order models obtained by applying a Petrov-Galerkin projection to all systems explaining the data characterized in a large-dimensional quadratic matrix inequality (QMI) can again be characterized in a lower-dimensional QMI. Next, we develop a data-driven generalized balanced truncation method that relies on two steps. First, we provide necessary and sufficient conditions such that systems explaining the data have common generalized Gramians. Second, these common generalized Gramians are used to construct matrices that allow to characterize a class of reduced-order models via generalized balanced truncation in terms of a lower-dimensional QMI by applying the data reduction concept. Additionally, we present alternative procedures to compute a priori and a posteriori upper bounds with respect to the true system generating the data. Finally, the proposed techniques are illustrated by means of application to an example of a system of a cart with a double-pendulum.

Contains fulltext : 292877.pdf (Publisher’s version ) (Open Access)

STUDY QUESTION For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception ( STUDY DESIGN, SIZE, DURATION We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception ( MAIN RESULTS AND THE ROLE OF CHANCE Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: −30% to −9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD −24%, 90% CI −36% to −13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S) The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER Dutch Trial register NL5455 (NTR5599) TRIAL REGISTRATION DATE 18 December 2015 DATE OF FIRST PATIENT’S ENROLMENT 26 January 2017

Glucose control in patients after total pancreatectomy is problematic because of the complete absence of α- and β-cells, leading to impaired quality of life. A novel, bihormonal artificial pancreas (BIHAP), using both insulin and glucagon, may improve glucose control, but studies in this setting are lacking.To assess the efficacy and safety of the BIHAP in patients after total pancreatectomy.This randomized crossover clinical trial compared the fully closed-loop BIHAP with current diabetes care (ie, insulin pump or pen therapy) in 12 adult outpatients after total pancreatectomy. Patients were recruited between August 21 and November 16, 2020. This first-in-patient study began with a feasibility phase in 2 patients. Subsequently, 12 patients were randomly assigned to 7-day treatment with the BIHAP (preceded by a 5-day training period) followed by 7-day treatment with current diabetes care, or the same treatments in reverse order. Statistical analysis was by Wilcoxon signed rank and Mann-Whitney U tests, with significance set at a 2-sided P.05.The primary outcome was the percentage of time spent in euglycemia (70-180 mg/dL [3.9-10 mmol/L]) as assessed by continuous glucose monitoring.In total, 12 patients (7 men and 3 women; median [IQR] age, 62.5 [43.1-74.0] years) were randomly assigned, of whom 3 did not complete the BIHAP phase and 1 was replaced. The time spent in euglycemia was significantly higher during treatment with the BIHAP (median, 78.30%; IQR, 71.05%-82.61%) than current diabetes care (median, 57.38%; IQR, 52.38%-81.35%; P = .03). In addition, the time spent in hypoglycemia (70 mg/dL [3.9 mmol/L]) was lower with the BIHAP (median, 0.00% [IQR, 0.00%-0.07%] vs 1.61% [IQR, 0.80%-3.81%]; P = .004). No serious adverse events occurred.Patients using the BIHAP after total pancreatectomy experienced an increased percentage of time in euglycemia and a reduced percentage of time in hypoglycemia compared with current diabetes care, without apparent safety risks. Larger randomized trials, including longer periods of treatment and an assessment of quality of life, should confirm these findings.trialregister.nl Identifier: NL8871.

BACKGROUND: Laparoscopic and robotic minimally invasive liver surgery (MILS) is gaining popularity. Recent data and views on the implementation of laparoscopic and robotic MILS throughout Europe are lacking.METHODS: An anonymous survey consisting of 46 questions was sent to all members of the European-African Hepato-Pancreato-Biliary Association.RESULTS: The survey was completed by 120 surgeons from 103 centers in 24 countries. Median annual center volume of liver resection was 100 [IQR 50-140]. The median annual volume of MILS per center was 30 [IQR 16-40]. For minor resections, laparoscopic MILS was used by 80 (67%) surgeons and robotic MILS by 35 (29%) surgeons. For major resections, laparoscopic MILS was used by 74 (62%) surgeons and robotic MILS by 33 (28%) surgeons. The majority of the surgeons stated that minimum annual volume of MILS per center should be around 21-30 procedures/year. Of the surgeons performing robotic surgery, 28 (70%) felt they missed specific equipment, such as a robotic-CUSA. Seventy (66%) surgeons provided a formal MILS training to residents and fellows. In 5 years' time, 106 (88%) surgeons felt that MILS would have superior value as compared to open liver surgery.CONCLUSION: In the participating European liver centers, MILS comprised about one third of all liver resections and is expected to increase further. Laparoscopic MILS is still twice as common as robotic MILS. Development of specific instruments for robotic liver parenchymal transection might further increase its adoption.

Background: In patients with familial adenomatous polyposis (FAP), extensive nonmalignant duodenal polyposis not amenable to endoscopic management demands surgical resection for which pancreas-preserving total duodenectomy (PPTD) offers a pancreatic parenchyma sparing approach. Methods: This is a retrospective cohort study including consecutive patients who underwent PPTD for FAP. Reconstruction involved a Billroth II anastomosis with a short isolated jejunal limb to facilitate future endoscopic surveillance. Short and long-term outcomes were evaluated. Results: Overall, 30 patients underwent PPTD for Spigelman stage III (n = 6) or IV (n = 24). Sixteen patients experienced a severe complication (Clavien–Dindo grade III/IV) including postoperative pancreatic fistula (ISGPS grade B/C) in twelve. There was no all cause in-hospital and 90-day mortality. During follow-up (median 125 months), five patients developed acute pancreatitis, one new-onset diabetes and one exocrine pancreatic insufficiency. During endoscopic surveillance in 27 patients, jejunal adenomas were detected in 22 and advanced adenomas in 11. An additional surgical resection was required in four patients with extensive jejunal polyposis. None developed jejunal cancer. The 10-year overall survival rate was 93.3%. Conclusion: Postoperative morbidity after PPTD is substantial but on the long-term, rates of pancreatic insufficiencies are low. Most patients develop jejunal adenomas at follow-up, highlighting the need for endoscopic surveillance.

Background: The use of robotic assistance in minimally invasive pancreatic resection is quickly growing. Methods: We present a systematic review of the literature regarding all types of robotic pancreatic resection (RPR). Our aim is to show for which procedures there is enough experience to permit safe training and provide an estimation of how many centers could serve as teaching institutions. Results: Sixty-four studies reporting on 4587 RPRs were analyzed. A total of 2598 pancreatoduodenectomies (PD) were reported by 28 centers from Europe (6/28; 21.4%), the Americas (11/28; 39.3%), and Asia (11/28; 39.3%). Six studies reported >100 robot PD (1694/2598; 65.2%). A total of 1618 distal pancreatectomies (DP) were reported by 29 centers from Europe (10/29; 34.5%), the Americas (10/29; 34.5%), and Asia (9/29; 31%). Five studies reported >100 robotic DP (748/1618; 46.2%). A total of 154 central pancreatectomies were reported by six centers from Europe (1/6; 16.7%), the Americas (2/6; 33.3%), and Asia (3/6; 50%). Only 49 total pancreatectomies were reported. Finally, 168 enucleations were reported in seven studies (with a mean of 15.4 cases per study). A single center reported on 60 enucleations (35.7%). Results of each type of robotic procedure are also presented. Conclusions: Experience with RPR is still quite limited. Despite high case volume not being sufficient to warrant optimal training opportunities, it is certainly a key component of every successful training program and is a major criterion for fellowship accreditation. From this review, it appears that only PD and DP can currently be taught at few institutions worldwide.

Liver regeneration is crucial to restore the functional liver mass after liver resection. The aim of this study was to evaluate the early postoperative changes in remnant liver function, volume and liver stiffness after major liver resection and their correlation with postoperative outcomes.Patients undergoing major liver resection (≥3 segments) between February and November 2018 underwent both functional assessment using technetium-99m mebrofenin hepatobiliary scintigraphy (HBS) and CT-volumetry of the (future) remnant liver on preoperative day 1, the 5A total of 18 patients were included of whom 10 (56%) had severe complications and one patient (5%) developed liver failure. Function and volume of the remnant liver had increased by the 5Functional regeneration of the remnant liver predominantly occurs during the first 5 days after resection. In case of severe complications, functional regeneration is delayed, in contrast to volume increase.

Switzerland introduced advanced wastewater treatment to reduce the release of micropollutants. Ozonation combined with additional post-treatment improves the quality of treated wastewater as measured with a variety of bioassays.

OBJECTIVE: To study the relationship between the steroid concentration in the endometrium, in serum, and the gene expression level of steroid-metabolizing enzymes in the context of endometrial receptivity in in vitro fertilization (IVF) patients.DESIGN: Case-control study of 40 IVF patients recruited in the SCRaTCH study (NTR5342), a randomized controlled trial investigating pregnancy outcome after "endometrial scratching." Endometrial biopsies and serum were obtained from patients with a first failed IVF cycle randomized to the endometrial scratch in the midluteal phase of the natural cycle before the next fresh embryo transfer during the second IVF cycle.SETTING: University hopsital.PATIENTS: Twenty women with clinical pregnancy were compared with 20 women who did not conceive after fresh embryo transfer. Cases and controls were matched for primary vs. secondary infertility, embryo quality, and age.INTERVENTION: None.MAIN OUTCOME MEASURE(S): Steroid concentrations in endometrial tissue homogenates and serum were measured with liquid chromatography-mass spectrometry. The endometrial transcriptome was profiled by RNA-sequencing, followed by principal component analysis and differential expression analysis. False discovery rate-adjusted and log-fold change >|0.5| were selected as the threshold for differentially expressed genes.RESULT(S): Estrogen levels were comparable in both serum (n = 16) and endometrium (n = 40). Androgens and 17-hydroxyprogesterone were higher in serum than that in endometrium. Although steroid levels did not vary between pregnant and nonpregnant groups, subgroup analysis of primary women with infertility showed a significantly lower estrone concentration and estrone:androstenedione ratio in serum of the pregnant group (n = 5) compared with the nonpregnant group (n = 2). Expression of 34 out of 46 genes encoding the enzymes controlling the local steroid metabolism was detected, and estrogen receptor β gene was differentially expressed between pregnant and nonpregnant women. When only the primary infertile group was considered, 28 genes were differentially expressed between pregnant and nonpregnant women, including HSD11B2, that catalyzes the conversion of cortisol into cortisone.CONCLUSION(S): Steroidomic and transcriptomic analyses show that steroid concentrations are regulated by the local metabolism in the endometrium. Although no differences were found in endometrial steroid concentration in the pregnant and nonpregnant IVF patients, primary women with infertility showed deviations in steroid levels and gene expression, indicating that a more homogeneous patient group is required to uncover the exact role of steroid metabolism in endometrial receptivity.CLINICAL TRIAL REGISTRATION NUMBER: The study was registered in the Dutch trial registry (www.trialregister.nl), registration number NL5193/NTR5342, available at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6687. The date of registration is July 31, 2015. The first enrollment is on January 1, 2016.

Background: Neoadjuvant treatment for pancreatic ductal adenocarcinoma (PDAC) has increased, necessitating histopathologic confirmation of cancer. This study evaluates the performance of endoscopic tissue acquisition (TA) procedures for borderline resectable and resectable PDAC. Methods: Pathology reports of patients included in two nationwide randomized controlled trials (PREOPANC and PREOPANC-2) were reviewed. The primary outcome was sensitivity for malignancy (SFM), considering both “suspicious for” and “malignant” as positive. Secondary outcomes were rate of adequate sampling (RAS) and diagnoses other than PDAC. Results: Overall, 892 endoscopic procedures were performed in 617 patients, including endoscopic ultrasonography (EUS)-guided TA in 550 (89.1%), endoscopic retrograde cholangiopancreatography (ERCP)-guided brush cytology in 188 (30.5%), and periampullary biopsies in 61 patients (9.9%). The SFM was 85.2% for EUS, 88.2% for repeat EUS, 52.7% for ERCP, and 37.7% for periampullary biopsies. The RAS ranged 94–100%. Diagnoses other than PDAC were other periampullary cancers in 24 (5.4%), premalignant disease in five (1.1%), and pancreatitis in three patients (0.7%). Conclusions: EUS-guided TA of patients with borderline resectable and resectable PDAC included in RCTs had an SFM above 85% for both first and repeat procedures, meeting international standards. Two percent had false positive result for malignancy and 5% had other (non-PDAC) periampullary cancers.

BACKGROUND: Robot-assisted distal pancreatectomy (RDP) is increasingly used as an alternative to laparoscopic distal pancreatectomy (LDP) in patients with resectable pancreatic cancer but comparative multicenter studies confirming the safety and efficacy of RDP are lacking. METHODS: An international, multicenter, retrospective, cohort study, including consecutive patients undergoing RDP and LDP for resectable pancreatic cancer in 33 experienced centers from 11 countries (2010-2019). The primary outcome was R0-resection. Secondary outcomes included lymph node yield, major complications, conversion rate, and overall survival. RESULTS: In total, 542 patients after minimally invasive distal pancreatectomy were included: 103 RDP (19%) and 439 LDP (81%). The R0-resection rate was comparable (75.7% RDP vs. 69.3% LDP, p = 0.404). RDP was associated with longer operative time (290 vs. 240 min, p < 0.001), more vascular resections (7.6% vs. 2.7%, p = 0.030), lower conversion rate (4.9% vs. 17.3%, p = 0.001), more major complications (26.2% vs. 16.3%, p = 0.019), improved lymph node yield (18 vs. 16, p = 0.021), and longer hospital stay (10 vs. 8 days, p = 0.001). The 90-day mortality (1.9% vs. 0.7%, p = 0.268) and overall survival (median 28 vs. 31 months, p = 0.599) did not differ significantly between RDP and LDP, respectively. CONCLUSIONS: In selected patients with resectable pancreatic cancer, RDP and LDP provide a comparable R0-resection rate and overall survival in experienced centers. Although the lymph node yield and conversion rate appeared favorable after RDP, LDP was associated with shorter operating time, less major complications, and shorter hospital stay. The specific benefits associated with each approach should be confirmed by multicenter, randomized trials.

Background: The COVID-19 pandemic has put substantial strain on the healthcare system of which the effects are only partly elucidated. This study aimed to investigate the impact on pancreatic cancer care. Methods: All patients diagnosed with pancreatic cancer between 2017 and 2020 were selected from the Netherlands Cancer Registry. Patients diagnosed and/or treated in 2020 were compared to 2017–2019. Monthly incidence was calculated. Patient, tumor and treatment characteristics were analyzed and compared using Chi-squared tests. Survival data was analyzed using Kaplan–Meier and Log-rank tests. Results: In total, 11019 patients were assessed. The incidence in quarter (Q)2 of 2020 was comparable with that in Q2 of 2017–2019 (p = 0.804). However, the incidence increased in Q4 of 2020 (p = 0.031), mainly due to a higher incidence of metastatic disease (p = 0.010). Baseline characteristics, surgical resection (15% vs 16%; p = 0.466) and palliative systemic therapy rates (23% vs 24%; p = 0.183) were comparable. In 2020, more surgically treated patients received (neo)adjuvant treatment compared to 2017–2019 (73% vs 67%; p = 0.041). Median overall survival was comparable (3.8 vs 3.8 months; p = 0.065). Conclusion: This nationwide study found a minor impact of the COVID-19 pandemic on pancreatic cancer care and outcome. The Dutch health care system was apparently able to maintain essential care for patients with pancreatic cancer.

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openaire: EC/H2020/856602/EU//FINEST TWINS For platoons under the multiple-predecessor following (MPF) topology, communication delays can compromise both the internal stability and string stability. The most straightforward solution to guarantee stability is by increasing the time headway. However, time headway plays a significant role in road capacity and increasing its value is in contrast with the idea of platooning. In this study, internal stability and string stability of platoons suffering from communication delays are investigated and a lower bound for the time headway is proposed. Using this bound, platoons do not need to massively increase the time headway in order to compensate for the effects of communications delays. Finally, we evaluate the proposed lower bound on the time headway and the simulation results demonstrate its effectiveness.

DNA methylation is important for establishing and maintaining cell identity and for genomic stability. This is achieved by regulating the accessibility of regulatory and transcriptional elements and the compaction of subtelomeric, centromeric, and other inactive genomic regions. Carcinogenesis is accompanied by a global loss in DNA methylation, which facilitates the transformation of cells. Cancer hypomethylation may also cause genomic instability, for example through interference with the protective function of telomeres and centromeres. However, understanding the role(s) of hypomethylation in tumor evolution is incomplete because the precise mutational consequences of global hypomethylation have thus far not been systematically assessed. Here we made genome-wide inventories of all possible genetic variation that accumulates in single cells upon the long-term global hypomethylation by CRISPR interference-mediated conditional knockdown of DNMT1. Depletion of DNMT1 resulted in a genomewide reduction in DNA methylation. The degree of DNA methylation loss was similar to that observed in many cancer types. Hypomethylated cells showed reduced proliferation rates, increased transcription of genes, reactivation of the inactive X-chromosome and abnormal nuclear morphologies. Prolonged hypomethylation was accompanied by increased chromosomal instability. However, there was no increase in mutational burden, enrichment for certain mutational signatures or accumulation of structural variation to the genome. In conclusion, the primary consequence of hypomethylation is genomic instability, which in cancer leads to increased tumor heterogeneity and thereby fuels cancer evolution.

Objective: Assessment of minimally invasive pancreatoduodenectomy (MIPD) in patients with pancreatic ductal adenocarcinoma (PDAC) is scarce and limited to non-randomized studies. This study aimed to compare oncological and surgical outcomes after MIPD compared to open pancreatoduodenectomy (OPD) for patients after resectable PDAC from published randomized controlled trials (RCTs). Methods: A systematic review was performed to identify RCTs comparing MIPD and OPD including PDAC (Jan 2015–July 2021). Individual data of patients with PDAC were requested. Primary outcomes were R0 rate and lymph node yield. Secondary outcomes were blood-loss, operation time, major complications, hospital stay and 90-day mortality. Results: Overall, 4 RCTs (all addressed laparoscopic MIPD) with 275 patients with PDAC were included. In total, 128 patients underwent laparoscopic MIPD and 147 patients underwent OPD. The R0 rate (risk difference(RD) −1%, P = 0.740) and lymph node yield (mean difference(MD) +1.55, P = 0.305) were comparable between laparoscopic MIPD and OPD. Laparoscopic MIPD was associated with less perioperative blood-loss (MD -91ml, P = 0.026), shorter length of hospital stay (MD -3.8 days, P = 0.044), while operation time was longer (MD +98.5 min, P = 0.003). Major complications (RD -11%, P = 0.302) and 90-day mortality (RD -2%, P = 0.328) were comparable between laparoscopic MIPD and OPD. Conclusions: This individual patient data meta-analysis of MIPD versus OPD in patients with resectable PDAC suggests that laparoscopic MIPD is non-inferior regarding radicality, lymph node yield, major complications and 90-day mortality and is associated with less blood loss, shorter hospital stay, and longer operation time. The impact on long-term survival and recurrence should be studied in RCTs including robotic MIPD.

Background: It has been suggested that fetal carcinogenic exposure might lead to predisposition to develop cancer during childhood or in later life possibly through modulation of the fetal transcriptome. Because gender effects in the incidence of childhood cancers have been described, we hypothesized differences at the transcriptomic level in cord blood between male and female newborns as a consequence of fetal carcinogenic exposure. The objective was to investigate whether transcriptomic responses to dietary genotoxic and nongenotoxic carcinogens show gender-specific mechanisms-of-action relevant for chemical carcinogenesis.Methods: Global gene expression was applied in umbilical cord blood samples, the CALUX-assay was used for measuring dioxin(-like), androgen(-like), and estrogen(-like) internal exposure, and acrylamide–hemoglobin adduct levels were determined by mass spectrometry adduct-FIRE-procedureTM. To link gene expression to an established phenotypic biomarker of cancer risk, micronuclei frequencies were investigated.Results: While exposure levels did not differ between sexes at birth, important gender-specific differences were observed in gene expressions associated with these exposures linked with cell cycle, the immune system and more general cellular processes such as posttranslation. Moreover, oppositely correlating leukemia/lymphoma genes between male and female newborns were identified in relation to the different biomarkers of exposure that might be relevant to male-specific predisposition to develop these cancers in childhood.Conclusions/Impact: This study reveals different transcriptomic responses to environmental carcinogens between the sexes. In particular, male-specific TNF-alpha-NF-kB signaling upon dioxin exposure and activation of the Wnt-pathway in boys upon acrylamide exposure might represent possible mechanistic explanations for gender specificity in the incidence of childhood leukemia. Cancer Epidemiol Biomarkers Prev; 21(10); 1756–67. ©2012 AACR.

PDF file, 40K, Complete list of GO terms, pathways and networks enriched among the significantly correlating genes using Tox-Profiler.

PDF file, 35K, Complete list of GO terms, pathways and networks enriched among the significantly correlating genes for the various biomarkers for females.

PDF file, 32K, Complete list of GO terms, pathways and networks enriched among the significantly correlating genes for the various biomarkers for males.

PDF file, 67K, Complete list of Human leukemia and lymphoma associated genes showing opposite correlations with biomarkers between male and female newborns.

Background Guidelines recommending antibiotic prophylaxis at emergency cholecystectomy for cholecystitis were based on low-quality evidence. The aim of this trial was to demonstrate that omitting antibiotics is not inferior to their prophylactic use. Methods This multicentre, randomized, open-label, non-inferiority clinical trial randomly assigned adults with mild-to-moderate acute calculous cholecystitis (immediate cholecystectomy indicated) to 2 g cefazolin administered before incision or no antibiotic prophylaxis. The primary endpoint was a composite of all postoperative infectious complications in the first 30 days after surgery. Secondary endpoints included all individual components of the primary endpoint, other morbidity, and duration of hospital stay. Results Sixteen of 226 patients (7.1 per cent) in the single-dose prophylaxis group and 29 of 231 (12.6 per cent) in the no-prophylaxis group developed postoperative infectious complications (absolute difference 5.5 (95 per cent c.i. −0.4 to 11.3) per cent). With a non-inferiority margin of 10 per cent, non-inferiority of no prophylaxis was not proven. The number of surgical-site infections was significantly higher in the no-prophylaxis group (5.3 versus 12.1 per cent; P = 0.010). No differences were observed in the number of other complications, or duration of hospital stay. Conclusion Omitting antibiotic prophylaxis is not recommended.

Contains fulltext : 251531.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To quantify the impact of individual complications on mortality, organ failure, hospital stay, and readmission after pancreatoduodenectomy. SUMMARY OF BACKGROUND DATA: An initial complication may provoke a sequence of adverse events potentially leading to mortality after pancreatoduodenectomy. This study was conducted to aid prioritization of quality improvement initiatives. METHODS: Data from consecutive patients undergoing pancreatoduodenectomy (2014-2017) were extracted from the Dutch Pancreatic Cancer Audit. Population attributable fractions (PAF) were calculated for the association of each complication (ie, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, wound infection, and pneumonia) with each unfavorable outcome [ie, in-hospital mortality, organ failure, prolonged hospital stay (>75th percentile), and unplanned readmission), whereas adjusting for confounders and other complications. The PAF represents the proportion of an outcome that could be prevented if a complication would be eliminated completely. RESULTS: Overall, 2620 patients were analyzed. In-hospital mortality occurred in 95 patients (3.6%), organ failure in 198 patients (7.6%), and readmission in 427 patients (16.2%). Postoperative pancreatic fistula and postpancreatectomy hemorrhage had the greatest independent impact on mortality [PAF 25.7% (95% CI 13.4-37.9) and 32.8% (21.9-43.8), respectively] and organ failure [PAF 21.8% (95% CI 12.9-30.6) and 22.1% (15.0-29.1), respectively]. Delayed gastric emptying had the greatest independent impact on prolonged hospital stay [PAF 27.6% (95% CI 23.5-31.8)]. The impact of individual complications on unplanned readmission was smaller than 11%. CONCLUSION: Interventions focusing on postoperative pancreatic fistula and postpancreatectomy hemorrhage may have the greatest impact on in-hospital mortality and organ failure. To prevent prolonged hospital stay, initiatives should in addition focus on delayed gastric emptying.

Contains fulltext : 283892.pdf (Publisher’s version ) (Closed access)

Background The number of elderly patients with pancreatic cancer is growing, however clinical data on the short-term outcomes, rate of adjuvant chemotherapy, and survival in these patients are limited and we therefore performed a nationwide analysis. Methods Data from the prospective Dutch Pancreatic Cancer Audit were analyzed, including all patients undergoing pancreatic cancer resection between January 2014 and December 2016. Patients were classified into two age groups: Results Of 836 patients, 198 were aged ≥75 years (24%) and 638 were aged p = 0.43) and 90-day mortality (8% vs. 5%; p = 0.18) did not differ. Adjuvant chemotherapy was started in 37% of patients aged ≥75 years versus 69% of patients aged p < 0.001). Median overall survival (OS) was 15 months (95% confidence interval [CI] 14–18) versus 21 months (95% CI 19–24; p < 0.001). Age ≥75 years was not independently associated with OS (hazard ratio 0.96, 95% CI 0.79–1.17; p = 0.71), but was associated with a lower rate of adjuvant chemotherapy (odds ratio 0.27, 95% CI 0.18–0.40; p < 0.001). Conclusions The rate of major complications and 90-day mortality after pancreatic resection did not differ between elderly and younger patients; however, elderly patients were less often treated with adjuvant chemotherapy and their OS was shorter.

IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence. Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.

OBJECTIVE: To perform a scoping review of imaging-based machine-learning models to predict clinical outcomes and identify biomarkers in patients with PDAC. SUMMARY OF BACKGROUND DATA: Patients with PDAC could benefit from better selection for systemic and surgical therapy. Imaging-based machine-learning models may improve treatment selection. METHODS: A scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses-scoping review guidelines in the PubMed and Embase databases (inception-October 2020). The review protocol was prospectively registered (open science framework registration: m4cyx). Included were studies on imaging-based machine-learning models for predicting clinical outcomes and identifying biomarkers for PDAC. The primary outcome was model performance. An area under the curve (AUC) of ≥0.75, or a P-value of ≤0.05, was considered adequate model performance. Methodological study quality was assessed using the modified radiomics quality score. RESULTS: After screening 1619 studies, 25 studies with 2305 patients fulfilled the eligibility criteria. All but 1 study was published in 2019 and 2020. Overall, 23/25 studies created models using radiomics features, 1 study quantified vascular invasion on computed tomography, and one used histopathological data. Nine models predicted clinical outcomes with AUC measures of 0.78-0.95, and C-indices of 0.65-0.76. Seventeen models identified biomarkers with AUC measures of 0.68-0.95. Adequate model performance was reported in 23/25 studies. The methodological quality of the included studies was suboptimal, with a median modified radiomics quality score score of 7/36. CONCLUSIONS: The use of imaging-based machine-learning models to predict clinical outcomes and identify biomarkers in patients with PDAC is increasingly rapidly. Although these models mostly have good performance scores, their methodological quality should be improved.

Background Delayed gastric emptying (DGE) is one of the most common complications following pancreatoduodenectomy (PD). In-hospital costs of DGE are unknown as well as the financial headroom for novel prophylactic treatments. This retrospective study aims to estimate the hospital costs of DGE and model the financial headroom per patient for new prophylactic treatment strategies within budget. Methods Retrospective analysis of a single-center prospective database including patients after PD (2010–2017). In-hospital costs for clinically relevant DGE (ISGPS grade B/C) were calculated by comparing patient groups with and without DGE or other complications. The financial headroom per patient was modelled for potential reductions (0–100%) of empirical DGE baseline risks (15–30%). Results Overall, DGE was present in 156 (26.9%) of 581 patients after PD. Costs for patients with isolated DGE (n = 90) were €10,295 higher than for patients without complications (n = 333). Costs for patients with other complications including DGE (n = 66) were €9008 higher than for patients with other complications without DGE (n = 92). The financial headroom for a novel prophylactic treatment per patient undergoing PD was €975 per 10% absolute decrease of DGE risk. Conclusion Hospital costs of DGE after PD are substantial. The financial headroom per patient for new DGE prophylactic treatments can be easily calculated via www.pancreascalculator.com.

Introduction The aim of this study was to develop a reliable objective structured assessment of technical skills (OSATS) score for linear-stapled, hand-sewn closure of enterotomy intestinal anastomoses (A-OSATS). Materials and methods The Delphi methodology was used to create a traditional and weighted A-OSATS score highlighting the more important steps for patient outcomes according to an international expert consensus. Minimally invasive novices, intermediates, and experts were asked to perform a minimally invasive linear-stapled intestinal anastomosis with hand-sewn closure of the enterotomy in a live animal model either laparoscopically or robot-assisted. Video recordings were scored by two blinded raters assessing intrarater and interrater reliability and discriminative abilities between novices (n = 8), intermediates (n = 24), and experts (n = 8). Results The Delphi process included 18 international experts and was successfully completed after 4 rounds. A total of 4 relevant main steps as well as 15 substeps were identified and a definition of each substep was provided. A maximum of 75 points could be reached in the unweighted A-OSATS score and 170 points in the weighted A-OSATS score respectively. A total of 41 anastomoses were evaluated. Excellent intrarater (r = 0.807–0.988, p p Conclusion With the weighted and unweighted A-OSATS score, we propose a new reliable standard to assess the creation of minimally invasive linear-stapled, hand-sewn anastomoses based on an international expert consensus. Validity evidence in live animal models is provided in this study. Future research should focus on assessing whether the weighted A-OSATS exceeds the predictive capabilities of patient outcomes of the unweighted A-OSATS and provide further validity evidence on using the score on different anastomotic techniques in humans.

One of the most popular methods for reducing the complexity of assemblies of finite element models in the field of structural dynamics is component mode synthesis. A main challenge of component mode synthesis is balancing model complexity and model accuracy, because it is difficult to predict how component reduction influences assembly model accuracy. This work introduces an approach that allows for the translation of assembly model accuracy requirements in the frequency domain to the automatic selection of the cut-off frequencies for the model-order reduction (MOR) of components. The approach is based on a mathematical approach for MOR for coupled linear systems in the field of systems and control. We show how this approach is also applicable to structural dynamics models. We demonstrate the use of this approach in the scope of component mode synthesis (CMS) methods with the aim to reduce the complexity of component models while guaranteeing accuracy requirements of the assembly model. The proposed approach is illustrated on a mechanical, three-component structural dynamics system for which reduced-order models are computed that are reduced further compared to reduction using standard methods. This results in lower simulation cost, while maintaining the required accuracy.

Background Centralization of pancreatic cancer surgery aims to improve postoperative outcomes. Consequently, patients with pancreatic cancer may undergo pancreatic surgery in an expert centre and adjuvant chemotherapy in a local hospital (network treatment). The aim of this study was to assess whether network treatment has an impact on time to chemotherapy, failure to complete adjuvant chemotherapy, and survival. Second, whether these parameters varied between pancreatic networks was studied. Methods This retrospective study included all patients diagnosed with non-metastatic pancreatic ductal adenocarcinoma who underwent pancreatic surgery and adjuvant chemotherapy, registered in the Netherlands Cancer Registry (2015–2020). Time to chemotherapy was defined as the time between surgery and the start of adjuvant chemotherapy. Completion of adjuvant chemotherapy was defined as the receipt of 12 cycles of FOLFIRINOX or six cycles of gemcitabine. Analysis was performed with linear mixed models and multilevel logistic regression models. Cox regression analyses were performed for survival. Results In total, 1074 patients were included. Network treatment was observed in 468 patients (43.6 per cent) and was not associated with longer time to chemotherapy (0.77 days, standard error (s.e.) 1.14, P = 0.501), failure to complete adjuvant chemotherapy (odds ratio (OR) = 1.140, 95 per cent c.i. 0.86 to 1.52, P = 0.349), and overall survival (hazards ratio (HR) = 1.04, 95 per cent c.i. 0.88 to 1.22, P = 0.640). Significant variation between the networks was observed for time to chemotherapy (range 40.5–63 days, P < 0.0001) and completion of adjuvant chemotherapy (range 19–52 per cent, P = 0.030). Adjusted for case mix, time to chemotherapy significantly differed between networks. Conclusion In this nationwide analysis, network treatment in patients with resected pancreatic cancer was not associated with longer time to chemotherapy, failure to complete adjuvant chemotherapy, and worse survival. Significant variation between pancreatic cancer networks was found for time to chemotherapy.

Additional file 1: Supplementary Table 1. Type of histological examinations performed and the distinction made based on all pathology reports.

Contains fulltext : 291512.pdf (Publisher’s version ) (Open Access) BACKGROUND: Surgical outcome after pancreatoduodenectomy for duodenal adenocarcinoma could differ from pancreatoduodenectomy for other cancers, but large multicenter series are lacking. This study aimed to determine surgical outcome in patients after pancreatoduodenectomy for duodenal adenocarcinoma, compared with other periampullary cancers, in a nationwide multicenter cohort. METHODS: After pancreatoduodenectomy for cancer between 2014 and 2019, consecutive patients were included from the nationwide, mandatory Dutch Pancreatic Cancer Audit. Patients were stratified by diagnosis. Baseline, treatment characteristics, and postoperative outcome were compared between groups. The association between diagnosis and major complications (Clavien-Dindo grade III or higher) was assessed via multivariable regression analysis. RESULTS: Overall, 3113 patients, after pancreatoduodenectomy for cancer, were included in this study: 264 (8.5%) patients with duodenal adenocarcinomas and 2849 (91.5%) with other cancers. After pancreatoduodenectomy for duodenal adenocarcinoma, patients had higher rates of major complications (42.8% vs. 28.6%; p

OBJECTIVE: The aim of this study was to explore the incidence, risk factors, clinical course and treatment of perforation and fistula of the gastrointestinal tract in a large unselected cohort of patients with necrotizing pancreatitis.SUMMARY BACKGROUND DATA: Perforation and fistula of the gastrointestinal (GI)-tract may occur in necrotizing pancreatitis. Data from large unselected patient populations on the incidence, risk factors, clinical outcomes, and treatment are lacking.METHODS: We performed a post-hoc analysis of a nationwide prospective database of 896 patients with necrotizing pancreatitis. GI-tract perforation and fistula were defined as spontaneous or iatrogenic discontinuation of the gastrointestinal wall. Multivariable logistic regression was used to explore risk factors and to adjust for confounders to explore associations of the GI-tract perforation and fistula on the clinical course.RESULTS: A perforation or fistula of the GI-tract was identified in 139 (16%) patients, located in the stomach in 23 (14%), duodenum in 56 (35%), jejunum or ileum in 18 (11%) and colon in 64 (40%). Risk factors were high C-reactive protein within 48-hours after admission (OR 1.19 [95%CI 1.01-1.39]) and early organ-failure (OR 2.76 [95%CI 1.78-4.29]). Prior invasive intervention was a risk factor for developing a perforation or fistula of the lower GI-tract (OR 2.60 [95% CI 1.04-6.60]). While perforation or fistula of the upper GI-tract appeared to be protective for persistent ICU-admission (OR 0.11 [95%CI 0.02-0.44]) and persistent organ failure (OR 0.15 [95%CI 0.02-0.58]), perforation or fistula of the lower GI-tract was associated with a higher rate of new onset organ failure (OR 2.47 [95%CI 1.23-4.84]). When the stomach or duodenum was affected, treatment was mostly conservative (n=54, 68%). Treatment was mostly surgical when the colon was affected (n=38, 59%).CONCLUSIONS: Perforation and fistula of the GI-tract occurred in one out of six patients with necrotizing pancreatitis. Risk factors were high C-reactive protein within 48 hours and early organ-failure. Prior intervention was identified as a risk factor for perforation or fistula of the lower GI-tract. The clinical course was mostly affected by involvement of the lower GI-tract.

Contains fulltext : 291514.pdf (Publisher’s version ) (Closed access) 01 april 2023

We present assume-guarantee contracts for continuous-time linear dynamical systems with inputs and outputs. These contracts are used to express specifications on the dynamic behaviour of a system. Contrary to existing approaches, we use simulation to compare the dynamic behaviour of two systems. This has the advantage of being supported by efficient numerical algorithms for verification as well as being related to the rich literature on (bi)simulation based techniques for verification and control, such as those based on (discrete) abstractions. Using simulation, we define contract implementation and a notion of contract refinement. We also define a notion of series composition for contracts, which allows us to reason about the series interconnection of systems on the basis of the contracts on its components. Together, the notions of refinement and composition allow contracts to be used for modular design and analysis of interconnected systems.

Contains fulltext : 238998.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pancreatic duct disruption or disconnection is a potentially severe complication of necrotizing pancreatitis. With no existing treatment guidelines, it is unclear whether there is any consensus among experts in clinical practice. We evaluated current expert opinion regarding the diagnosis and treatment of pancreatic duct disruption and disconnection in an international case vignette study. METHODS: An online case vignette survey was sent to 110 international expert pancreatologists. Expert selection was based on publications in the last 5 years and/or participation in development of IAP/APA and ESGE guidelines on acute pancreatitis. Consensus was defined as agreement by at least 75% of the experts. RESULTS: The response rate was 51% (n = 56). Forty-four experts (79%) obtained a MRI/MRCP and 52 experts (93%) measured amylase levels in percutaneous drain fluid to evaluate pancreatic duct integrity. The majority of experts favored endoscopic transluminal drainage for infected (peri)pancreatic necrosis and pancreatic duct disruption (84%, n = 45) or disconnection (88%, n = 43). Consensus was lacking regarding the treatment of patients with persistent percutaneous drain production, and with persistent sterile necrosis. CONCLUSION: This international survey of experts demonstrates that there are many areas for which no consensus existed, providing clear focus for future investigation.

In this contribution I attempt to explain why so many fundamental controversies surrounding the provision on national identity have not been nearly resolved ten years after the entry into force of the Lisbon Treaty. Also, I indicate why these problems and controversies can be expected to linger on for at least the next ten years. Constitutional identity, EU law, constitutional law, EU member states