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BACKGROUND: For palliative drainage of inoperable perihilar cholangiocarcinoma (pCCA) uncovered metal stents are preferred over plastic stents. However, there is a lack of data on re-interventions at the long-term. The aim is to evaluate the potential difference in the number of re-interventions in patients surviving at least 6 months.METHODS: Retrospective study including patients with pCCA who underwent plastic stent placement(s) or had metal stent(s) in situ for at least 6 months. The primary outcome was the number of re-interventions per patient-year. A propensity score matching (1:1) analysis was performed using age, Bismuth classification, reason for inoperability, pathological confirmation, systemic therapy and initial approach (endoscopic vs percutaneous).RESULTS: Patients in the metal stent group (n = 87) underwent fewer re-interventions compared with the plastic stent group (n = 40) (3.0 vs. 4.7 per patient-year; IRR, 0.64; 95% CI, 0.47 to 0.88). When only non-elective re-interventions were included, there was no significant difference (2.1 vs. 2.7; IRR, 0.76; 95% CI, 0.55 to 1.08). Results were similar in the propensity score-matched dataset.CONCLUSIONS: This study shows that, also in patients with inoperable pCCA who survive at least 6 months, placement of metal stent(s) leads to fewer re-interventions in comparison with plastic stents.

Background Selective lymphadenectomy using sentinel node-navigated surgery (SNNS) might offer a less invasive alternative to esophagectomy in patients with high-risk T1 esophageal adenocarcinoma (EAC). The aim of this study was to evaluate the feasibility and safety of a new treatment strategy, consisting of radical endoscopic resection of the tumor followed by SNNS. Methods In this multicenter pilot study, ten patients with a radically resected high-risk pT1cN0 EAC underwent SNNS. A hybrid tracer of technetium-99m nanocolloid and indocyanine green was injected endoscopically around the resection scar the day before surgery, followed by preoperative imaging. During surgery, sentinel nodes (SNs) were identified using a thoracolaparoscopic gammaprobe and fluorescence-based detection, and subsequently resected. Endpoints were surgical morbidity and number of detected and resected (tumor-positive) SNs. Results Localization and dissection of SNs was feasible in all ten patients (median 3 SNs per patient, range 1–6). The concordance between preoperative imaging and intraoperative detection was high. In one patient (10%), dissection was considered incomplete after two SNs were not identified intraoperatively. Additional peritumoral SNs were resected in four patients (40%) after fluorescence-based detection. In two patients (20%), a (micro)metastasis was found in one of the resected SNs. One patient experienced neuropathic thoracic pain related to surgery, while none of the patients developed functional gastroesophageal disorders. Conclusions SNNS appears to be a feasible and safe instrument to tailor lymphadenectomy in patients with high-risk T1 EAC. Future research with long-term follow-up is warranted to determine whether this esophageal preserving strategy is justified for high-risk T1 EAC.

Background: Difficulty scoring systems are important for the safe, stepwise implementation of new procedures. We designed a retrospective observational study for building a difficulty score for robotic pancreatoduodenectomy. Methods: The difficulty score (PD-ROBOSCORE) aims at predicting severe postoperative complications after robotic pancreatoduodenectomy. The PD-ROBOSCORE was developed in a training cohort of 198 robotic pancreatoduodenectomies and was validated in an international multicenter cohort of 686 robotic pancreatoduodenectomies. Finally, all centers tested the model during the early learning curve (n = 300). Growing difficulty levels (low, intermediate, high) were defined using cut-off values set at the 33rd and 66th percentile (NCT04662346). Results: Factors included in the final multivariate model were a body mass index of ≥25 kg/m2 for males and ≥30 kg/m2 for females (odds ratio:2.39; P < .0001), borderline resectable tumor (odd ratio:1.98; P < .0001), uncinate process tumor (odds ratio:1.69; P < .0001), pancreatic duct size

Aims There is considerable controversy regarding optimal management of patients with paraesophageal hiatus hernia (pHH). This survey aims at identifying recommended strategies for work-up, surgical therapy, and postoperative follow-up using Delphi methodology. Methods We conducted a 2-round, 33-question, web-based Delphi survey on perioperative management (preoperative work-up, surgical procedure and follow-up) of non-revisional, elective pHH among European surgeons with expertise in upper-GI. Responses were graded on a 5-point Likert scale and analyzed using descriptive statistics. Items from the questionnaire were defined as “recommended” or “discouraged” if positive or negative concordance among participants was > 75%. Items with lower concordance levels were labelled “acceptable” (neither recommended nor discouraged). Results Seventy-two surgeons with a median (IQR) experience of 23 (14–30) years from 17 European countries participated (response rate 60%). The annual median (IQR) individual and institutional caseload was 25 (15–36) and 40 (28–60) pHH-surgeries, respectively. After Delphi round 2, “recommended” strategies were defined for preoperative work-up (endoscopy), indication for surgery (typical symptoms and/or chronic anemia), surgical dissection (hernia sac dissection and resection, preservation of the vagal nerves, crural fascia and pleura, resection of retrocardial lipoma) and reconstruction (posterior crurorrhaphy with single stitches, lower esophageal sphincter augmentation (Nissen or Toupet), and postoperative follow-up (contrast radiography). In addition, we identified “discouraged” strategies for preoperative work-up (endosonography), and surgical reconstruction (crurorrhaphy with running sutures, tension-free hiatus repair with mesh only). In contrast, many items from the questionnaire including most details of mesh augmentation (indication, material, shape, placement, and fixation technique) were “acceptable”. Conclusions This multinational European Delphi survey represents the first expert-led process to identify recommended strategies for the management of pHH. Our work may be useful in clinical practice to guide the diagnostic process, increase procedural consistency and standardization, and to foster collaborative research.

Objective: The Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. Design & methods: NBS data and parameters of CH patients and false-positive referrals in the period 2007–2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. Results: Variables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. Conclusions: Machine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.

Background: Anastomotic suturing is the Achilles heel of pancreatic surgery. Especially in laparoscopic and robotically assisted surgery, the pancreatic anastomosis should first be trained outside the operating room. Realistic training models are therefore needed. Methods: Models of the pancreas, small bowel, stomach, bile duct, and a realistic training torso were developed for training of anastomoses in pancreatic surgery. Pancreas models with soft and hard textures, small and large ducts were incrementally developed and evaluated. Experienced pancreatic surgeons (n = 44) evaluated haptic realism, rigidity, fragility of tissues, and realism of suturing and knot tying. Results: In the iterative development process the pancreas models showed high haptic realism and highest realism in suturing (4.6 ± 0.7 and 4.9 ± 0.5 on 1–5 Likert scale, soft pancreas). The small bowel model showed highest haptic realism (4.8 ± 0.4) and optimal wall thickness (0.1 ± 0.4 on −2 to +2 Likert scale) and suturing behavior (0.1 ± 0.4). The bile duct models showed optimal wall thickness (0.3 ± 0.8 and 0.4 ± 0.8 on −2 to +2 Likert scale) and optimal tissue fragility (0 ± 0.9 and 0.3 ± 0.7). Conclusion: The biotissue training models showed high haptic realism and realistic suturing behavior. They are suitable for realistic training of anastomoses in pancreatic surgery which may improve patient outcomes.

Background In addition to the reduction of symptomatic gallstone disease, ursodeoxycholic acid (UDCA) might also have beneficial metabolic effects after bariatric surgery. We examined the impact of UDCA on liver enzymes, hemoglobin A1c (HbA1c), lipids, and inflammation markers. Methods Patients in the UPGRADE trial (placebo-controlled, double-blind) were randomized between UDCA 900 mg daily or placebo pills for 6 months after bariatric surgery. Patients without blood measurements pre- or 6 months postoperatively were excluded. The change in liver enzymes, Hba1c, lipids, and inflammation markers after surgery were compared between the UDCA and placebo group, followed by a postoperative cross-sectional comparison. Results In total, 513 patients were included (age [mean ± SD] 45.6 ± 10.7 years; 79% female). Preoperative blood values did not differ between UDCA (n = 266) and placebo (n = 247) groups. Increase of alkaline phosphatase (ALP) was greater in the UDCA group (mean difference 3.81 U/l [95%CI 0.50 7.12]). Change in other liver enzymes, HbA1c, lipids, and CRP levels did not differ. Postoperative cross-sectional comparison in 316 adherent patients also revealed a higher total cholesterol (mean difference 0.25 mg/dl [95%CI 0.07–0.42]), lower aspartate aminotransferase (mean difference −3.12 U/l [−5.16 – −1.08]), and lower alanine aminotransferase level (mean difference −5.89 U/l [−9.41 – −2.37]) in the UDCA group. Conclusion UDCA treatment leads to a higher, but clinically irrelevant increase in ALP level in patients 6 months after bariatric surgery. No other changes in metabolic or inflammatory markers were observed. Except for the reduction of gallstone formation, UDCA has no effects after bariatric surgery. Graphical Abstract

Background Endoscopic retrograde cholangiopancreatography (ERCP) with biliary brush cytology is commonly used to diagnose malignant pancreatobiliary strictures. This trial compared the sensitivity of two intraductal brush cytology devices. Methods A randomized controlled trial in which consecutive patients with suspected malignant, extrahepatic biliary strictures were randomized (1:1) to a dense or conventional brush cytology device. Primary endpoint was sensitivity. Interim analysis was conducted after 50% of the patients completed follow-up. Results were interpreted by a data safety monitoring board. Results Between June 2016 and June 2021, 64 patients were randomized to the dense (27 patients, 42%) or conventional brush (37 patients, 58%). Malignancy was diagnosed in 60 patients (94%) and benign disease in 4 patients (6%). Diagnoses were confirmed by histopathology in 34 patients (53%), cytopathology in 24 patients (38%), and clinical or radiological follow up in 6 patients (9%). Sensitivity of the dense brush was 50%, compared to 44% for the conventional brush (p = 0·785). Discussion The results of this randomized controlled trial showed that the sensitivity of a dense brush is not superior to a conventional brush for diagnosing malignant extrahepatic pancreatobiliary strictures. This trial was prematurely ended for reasons of futility. Trial registration Netherlands Trial Register number; NTR5458.

BACKGROUND: The role of laparoscopy for emergency resection of left-sided obstructive colon cancer remains unclear, especially regarding impact on survival. OBJECTIVE: This study aimed to determine short- and long-term outcomes after laparoscopic versus open emergency resection of left-sided obstructive colon cancer. DESIGN: This observational cohort study compared patients who underwent laparoscopic emergency resection to those who underwent open emergency resection between 2009 and 2016 by using 1:3 propensity-score matching. Matching variables included sex, age, BMI, ASA score, previous abdominal surgery, tumor location, cT4, cM1, multivisceral resection, small-bowel distention on CT, and subtotal colectomy. SETTING: This was a nationwide, population-based study. PATIENTS: Of 2002 eligible patients with left-sided obstructive colon cancer, 158 patients who underwent laparoscopic emergency resection were matched with 474 patients who underwent open emergency resection. INTERVENTIONS: The intervention was laparoscopic versus open emergency resection. MAIN OUTCOME MEASURES: The main outcome measures were 90-day mortality, 90-day complications, permanent stoma, disease recurrence, overall survival, and disease-free survival. RESULTS: Intentional laparoscopy resulted in significantly fewer 90-day complications (26.6% vs 38.4%; conditional OR, 0.59; 95% CI, 0.39-0.87) and similar 90-day mortality. Laparoscopy resulted in better 3-year overall survival (81.0% vs 69.4%; HR, 0.54; 95% CI, 0.37-0.79) and disease-free survival (68.3% vs 52.3%; HR, 0.64; 95% CI, 0.47-0.87). Multivariable regression analyses of the unmatched 2002 patients confirmed an independent association of laparoscopy with fewer 90-day complications and better 3-year survival. LIMITATIONS: Selection bias was the limitation that cannot be completely ruled out because of the retrospective nature of this study. CONCLUSIONS: This population-based study with propensity score-matched analysis suggests that intentional laparoscopic emergency resection might improve outcomes in patients with left-sided obstructive colon cancer compared to open emergency resection. Management of those patients in the emergency setting requires proper selection for intentional laparoscopic resection if relevant expertise is available, thereby considering other alternatives to avoid open emergency resection (ie, decompressing stoma).

SP140 is an epigenetic reader protein expressed predominantly in immune cells. GWAS studies have shown an association between SP140 single nucleotide polymorphisms (SNPs) and diverse autoimmune and inflammatory diseases, suggesting a possible pathogenic role for SP140 in immune-mediated diseases. We previously demonstrated that treatment of human macrophages with the novel selective inhibitor of the SP140 protein (GSK761) reduced the expression of endotoxin-induced cytokines, implicating a role of SP140 in the function of inflammatory macrophages. In this study, we investigated the effects of GSK761 on in vitro human dendritic cell (DC) differentiation and maturation, assessing the expression of cytokines and co-stimulatory molecules and their capacity to stimulate T-cell activation and induce phenotypic changes. In DCs, lipopolysaccharide (LPS) stimulation induced an increase in SP140 expression and its recruitment to transcription start sites (TSS) of pro-inflammatory cytokine genes. Moreover, LPS-induced cytokines such as TNF, IL-6, and IL-1β were reduced in GSK761- or SP140 siRNA- treated DCs. Although GSK761 did not significantly affect the expression of surface markers that define the differentiation of CD14+ monocytes into immature DCs (iDCs), subsequent maturation of iDCs to mature DCs was significantly inhibited. GSK761 strongly reduced expression of the maturation marker CD83, the co-stimulatory molecules CD80 and CD86, and the lipid-antigen presentation molecule CD1b. Finally, when the ability of DCs to stimulate recall T-cell responses by vaccine-specific T cells was assessed, T cells stimulated by GSK761-treated DCs showed reduced TBX21 and RORA expression and increased FOXP3 expression, indicating a preferential generation of regulatory T cells. Overall, this study suggests that SP140 inhibition enhances the tolerogenic properties of DCs, supporting the rationale of targeting SP140 in autoimmune and inflammatory diseases where DC-mediated inflammatory responses contribute to disease pathogenesis.

Aim: To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double-blind placebo-controlled trial in abdominally obese individuals. Materials and methods: Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m 2) were randomized to an 8-week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, β-cell function, insulin-mediated microvascular recruitment, skin microvascular function, flow-mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra-performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one-way ANCOVA. Results: In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule-1 (sVCAM-1) in the low and high PM dose group and of soluble intercellular adhesion molecule-1 (sICAM-1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. Conclusions: This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM-1 and sICAM-1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis.

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.

Microbial cell factories face changing environments during industrial fermentations. Kinetic metabolic models enable the simulation of the dynamic metabolic response to these perturbations, but their development is challenging due to model complexity and experimental data requirements. An example of this is the well-established microbial cell factory Saccharomyces cerevisiae, for which no consensus kinetic model of central metabolism has been developed and implemented in industry. Here, we aim to bring the academic and industrial communities closer to this consensus model. We developed a physiology informed kinetic model of yeast glycolysis connected to central carbon metabolism by including the effect of anabolic reactions precursors, mitochondria and the trehalose cycle. To parametrize such a large model, a parameter estimation pipeline was developed, consisting of a divide and conquer approach, supplemented with regularization and global optimization. Additionally, we show how this first mechanistic description of a growing yeast cell captures experimental dynamics at different growth rates and under a strong glucose perturbation, is robust to parametric uncertainty and explains the contribution of the different pathways in the network. Such a comprehensive model could not have been developed without using steady state and glucose perturbation data sets. The resulting metabolic reconstruction and parameter estimation pipeline can be applied in the future to study other industrially-relevant scenarios. We show this by generating a hybrid CFD-metabolic model to explore intracellular glycolytic dynamics for the first time. The model suggests that all intracellular metabolites oscillate within a physiological range, except carbon storage metabolism, which is sensitive to the extracellular environment.

Objectives: Preventive measures against COVID-19 are essential for pregnant women. Pregnant women are particularly vulnerable to emerging infectious pathogens due to alterations in their physiology. We aimed to determine the optimum timing of vaccination to protect pregnant women and their neonates from COVID-19. Methods: A prospective observational longitudinal cohort study in pregnant women who received COVID-19 vaccination. We collected blood samples to evaluate levels of antispike, receptor binding domain and nucleocapsid antibodies against SARS-CoV-2 before vaccination and 15 days after the first and second vaccination. We determined the neutralizing antibodies from mother-infant dyads in maternal and umbilical cord blood at birth. If available, immunoglobulin A was measured in human milk. Results: We included 178 pregnant women. Median antispike immunoglobulin G levels increased significantly from 1.8 to 5431 binding antibody units/ml and receptor binding domain from 6 to 4466 binding antibody units/ml. Virus neutralization showed similar results between different weeks of gestation at vaccination (P >0.3). Conclusion: We advise vaccination in the early second trimester of pregnancy for the optimum balance between the maternal antibody response and placental antibody transfer to the neonate.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p

OBJECTIVE: Limited sampling strategies (LSS) lower the burden of pharmacokinetic (PK)-guided dosing, but an extensive evaluation of LSS for BAX 855 (Adynovi) is currently lacking. This study aimed to develop a LSS for BAX 855 and combine this with a LSS of a standard half-life (SHL) factor VIII (FVIII) concentrate in a clinical setting. METHODS: Individual PK parameters of BAX 855 were estimated for 10 000 virtual patients with severe hemophilia A using Monte Carlo simulations. Several LSS consisting of 2-6 samples were examined based on patient burden, bias and accuracy of clearance, elimination half-life, volume of distribution and trough levels at 72 h (C72). Analyses were performed separately for adults and children

Background: Acute mesenteric ischaemia (AMI) is a condition with high mortality. This survey assesses current attitudes and practices to manage AMI worldwide.Methods: A questionnaire survey about the practices of diagnosing and managing AMI, endorsed by several specialist societies, was sent to different medical specialists and hospitals worldwide. Data from individual health care professionals and from medical teams were collected.Results: We collected 493 individual forms from 71 countries and 94 team forms from 34 countries. Almost half of respondents were surgeons, and most of the responding teams (70%) were led by surgeons. Most of the respondents indicated that diagnosis of AMI is often delayed but rarely missed. Emergency revascularisation is often considered for patients with AMI but rarely in cases of transmural ischaemia (intestinal infarction). Responses from team hospitals with a dedicated special unit (14 team forms) indicated more aggressive revascularisation. Abdominopelvic CT-scan with intravenous contrast was suggested as the most useful diagnostic test, indicated by approximately 90% of respondents. Medical history and risk factors were thought to be more important in diagnosis of AMI without transmural ischaemia, whereas for intestinal infarction, plasma lactate concentrations and surgical exploration were considered more useful. In elderly patients, a palliative approach is often chosen over extensive bowel resection. There was a large variability in anticoagulant treatment, as well as in timing of surgery to restore bowel continuity.Conclusions: Delayed diagnosis of AMI is common despite wide availability of an adequate imaging modality, i.e. CT-scan. Large variability in treatment approaches exists, indicating the need for updated guidelines. Increased awareness and knowledge of AMI may improve current practice until more robust evidence becomes available. Adherence to the existing guidelines may help in improving differences in treatment and outcomes. Background: Acute mesenteric ischaemia (AMI) is a condition with high mortality. This survey assesses current attitudes and practices to manage AMI worldwide.Methods: A questionnaire survey about the practices of diagnosing and managing AMI, endorsed by several specialist societies, was sent to different medical specialists and hospitals worldwide. Data from individual health care professionals and from medical teams were collected.Results: We collected 493 individual forms from 71 countries and 94 team forms from 34 countries. Almost half of respondents were surgeons, and most of the responding teams (70%) were led by surgeons. Most of the respondents indicated that diagnosis of AMI is often delayed but rarely missed. Emergency revascularisation is often considered for patients with AMI but rarely in cases of transmural ischaemia (intestinal infarction). Responses from team hospitals with a dedicated special unit (14 team forms) indicated more aggressive revascularisation. Abdominopelvic CT-scan with intravenous contrast was suggested as the most useful diagnostic test, indicated by approximately 90% of respondents. Medical history and risk factors were thought to be more important in diagnosis of AMI without transmural ischaemia, whereas for intestinal infarction, plasma lactate concentrations and surgical exploration were considered more useful. In elderly patients, a palliative approach is often chosen over extensive bowel resection. There was a large variability in anticoagulant treatment, as well as in timing of surgery to restore bowel continuity.Conclusions: Delayed diagnosis of AMI is common despite wide availability of an adequate imaging modality, i.e. CT-scan. Large variability in treatment approaches exists, indicating the need for updated guidelines. Increased awareness and knowledge of AMI may improve current practice until more robust evidence becomes available. Adherence to the existing guidelines may help in improving differences in treatment and outcomes.

Item does not contain fulltext OBJECTIVE: To evaluate the learning curve of laparoscopic gastrectomy (LG) after an implementation program. BACKGROUND: Although LG is increasingly being performed worldwide, little is known about the learning curve. METHODS: Consecutive patients who underwent elective LG for gastric adenocarcinoma with curative intent in each of the 5 highest-volume centers in the Netherlands were enrolled. Generalized additive models and a 2-piece model with a break point were used to determine the learning curve length. Analyses were corrected for casemix and were performed for LG and for the subgroups distal gastrectomy (LDG) and total gastrectomy (LTG). The learning curve effect was assessed for (1) anastomotic leakage; and (2) the occurrence of postoperative complications, conversions to open surgery, and short-term oncological parameters. RESULTS: In total 540 patients were included for analysis, 108 patients from each center; 268 patients underwent LDG and 272 underwent LTG. First, for LG, no learning effect regarding anastomotic leakage could be identified: the rate of anastomotic leakage initially increased, then reached a plateau after 36 cases at 10% anastomotic leakage. Second, the level of overall complications reached a plateau after 20 cases, at 38% overall complications, and at 5% conversions. For both LDG and LTG, each considered separately, fluctuations in secondary outcomes and anastomotic leakage followed fluctuations in casemix. CONCLUSION: On the basis of our study of the first 108 procedures of LG in 5 high-volume centers with well-trained surgeons, no learning curve effect could be identified regarding anastomotic leakage. A learning curve effect was found with respect to overall complications and conversion rate.

Background and Objective: Whether benefits and risks of intravenous (IV) infliximab combotherapy with immunosuppressants versus infliximab monotherapy apply to subcutaneous (SC) infliximab is unknown. This post hoc analysis of a pivotal randomised CT-P13 SC 1.6 trial aimed to compare SC infliximab monotherapy with combotherapy in inflammatory bowel disease (IBD). Methods: Biologic-naïve patients with active Crohn’s disease or ulcerative colitis received CT-P13 IV 5 mg/kg at Week (W) 0 and 2 (dose-loading phase). At W6, patients were randomised (1:1) to receive CT-P13 SC 120 or 240 mg (patients 0.999) or meeting efficacy or biomarker outcomes including clinical remission (62.9% vs 74.1%; p = 0.418). Monotherapy and combotherapy groups had comparable immunogenicity (anti-drug antibodies [ADAs]: 65.5% vs 48.0% [p = 0.271], neutralising antibodies [in ADA-positive patients]: 10.5% vs 16.7% [p = 0.630], respectively). Conclusions: Pharmacokinetics, efficacy and immunogenicity were potentially comparable between SC infliximab monotherapy and combotherapy in biologic-naïve IBD patients. Trial Registration: ClinicalTrials.gov: NCT02883452. Graphical Abstract: [Figure not available: see fulltext.]

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.

BACKGROUND: The European registry for minimally invasive pancreatic surgery (E-MIPS) collects data on laparoscopic and robotic MIPS in low- and high-volume centers across Europe.METHODS: Analysis of the first year (2019) of the E-MIPS registry, including minimally invasive distal pancreatectomy (MIDP) and minimally invasive pancreatoduodenectomy (MIPD). Primary outcome was 90-day mortality.RESULTS: Overall, 959 patients from 54 centers in 15 countries were included, 558 patients underwent MIDP and 401 patients MIPD. Median volume of MIDP was 10 (7-20) and 9 (2-20) for MIPD. Median use of MIDP was 56.0% (IQR 39.0-77.3%) and median use of MIPD 27.7% (IQR 9.7-45.3%). MIDP was mostly performed laparoscopic (401/558, 71.9%) and MIPD mostly robotic (234/401, 58.3%). MIPD was performed in 50/54 (89.3%) centers, of which 15/50 (30.0%) performed ≥20 MIPD annually. This was 30/54 (55.6%) centers and 13/30 (43%) centers for MIPD respectively. Conversion rate was 10.9% for MIDP and 8.4% for MIPD. Overall 90 day mortality was 1.1% (n = 6) for MIDP and 3.7% (n = 15) for MIPD.CONCLUSION: Within the E-MIPS registry, MIDP is performed in about half of all patients, mostly using laparoscopy. MIPD is performed in about a quarter of patients, slightly more often using the robotic approach. A minority of centers met the Miami guideline volume criteria for MIPD.

Purpose: Our purpose was to assess the prevalence of patient-reported symptoms of local late toxicity in patients with irradiated breast cancer and determine the association between late toxicity and quality of life. Methods: Within the prospective Utrecht cohort for Multiple BReast cancer intErvention studies and Long-term evaluation cohort, a survey on self-reported late toxicity was sent to all patients with breast cancer with ≥12 months interval since radiation therapy treated with curative intent. Patients were treated with hypofractionated radiation therapy of 40 Gy/15 fractions or 42.5 Gy/16 fractions, with or without a simultaneous integrated boost. Symptoms of late toxicity were evaluated on a 4-point Likert scale. Late toxicity was defined as moderate-severe breast or chest wall pain combined with at least 1 other mild-severe late toxicity symptom, that is, breast or arm/hand lymphedema, firmness of the breast, or impaired arm movement. Physical, role, and social functioning were measured before, during, and after the late toxicity survey using the European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire-C30 and compared with a Dutch normative population. Results: In the study, 1613/2248 patients (72%) were included. Of those, 16% (n = 265) reported late toxicity. The median time interval between radiation therapy and survey was 38 months (interquartile range, 21-55). Moderate/severe firmness of the breast, chest wall pain, and breast pain were reported by, respectively, 18% (n = 295), 14% (n = 225), and 10% (n = 140) of all patients. Physical, role, and social functioning were below the clinical threshold (ie, clinically relevant impairment) in 13% to 52% of patients with late toxicity and 2% to 26% of patients without late toxicity. Patients with late toxicity significantly more often received analgesics, physiotherapy, and lymphedema therapy compared with patients without late toxicity. Conclusions: This study provided insight into the prevalence of patient-reported late toxicity after hypofractionated radiation therapy and the influence of late toxicity on quality of life after breast cancer. These results may help health care professionals to inform their patients about long-term effects of breast cancer treatment including hypofractionated radiation therapy.

Aim Necrotizing enterocolitis (NEC) is the most lethal disease of the gastrointestinal tract of preterm infants. New and existing management strategies need clinical evaluation. Large heterogeneity exists in the selection, measurement, and reporting of outcome measures in NEC intervention studies. This hampers meta-analyses and the development of evidence-based management guidelines. We aim to develop a Core Outcome Set (COS) for NEC that includes the most relevant outcomes for patients and physicians, from moment of diagnosis into adulthood. This COS is designed for use in NEC treatment trials, in infants with confirmed NEC. Methods This study is designed according to COS-STAD (Core Outcome Set-STAndards for Development) recommendations and the COMET (Core Outcome Measures in Effectiveness Trials) Initiative Handbook. We obtained a waiver from the Ethics Review Board and prospectively registered this study with COMET (Study 1920). We will approach 125 clinicians and/or researchers from low-middle and high-income countries based on their scientific output (using SCIVAL, a bibliometric tool). Patients and parents will be approached through local patient organisations. Participants will be separated into three panels, to assess differences in priorities between former patients and parents (1. lay panel), clinicians and researchers involved in the neonatal period (2. neonatal panel) and after the neonatal period (3. post-neonatal panel). They will be presented with outcomes currently used in NEC research, identified through a systematic review, in a Delphi process. Eligible outcome domains are also identified from the patients and parents’ perspectives. Using a consensus process, including three online Delphi rounds and a final face-to-face consensus meeting, the COS will be finalised and include outcomes deemed essential to all stakeholders: health care professionals, parents and patients’ representatives. The final COS will be reported in accordance with the COS-Standards for reporting (COS-STAR) statement. Conclusions Development of an international COS will help to improve homogeneity of outcome measure reporting in NEC, will enable adequate and efficient comparison of treatment strategies, and will help the interpretation and implementation of clinical trial results. This will contribute to high-quality evidence regarding the best treatment strategy for NEC in preterm infants.

INTRODUCTION: Haemorrhoidal disease (HD) is a common condition with significant epidemiologic and economic implications. While it is possible to treat symptomatic grade 1-2 haemorrhoids with rubber band ligation (RBL) or sclerotherapy (SCL), the effectiveness of these treatments compatible with current standards has not yet been investigated with a randomised controlled trial. The hypothesis is that SCL is not inferior to RBL in terms of symptom reduction (patient-related outcome measures (PROMs)), patient experience, complications or recurrence rate. METHODS AND ANALYSIS: This protocol describes the methodology of a non-inferiority, multicentre, randomised controlled trial comparing rubber band ligation and sclerotherapy for symptomatic grade 1-2 haemorrhoids in adults (> 18 years). Patients are preferably randomised between the two treatment arms. However, patients with a strong preference for one of the treatments and refuse randomisation are eligible for the registration arm. Patients either receive 4 cc Aethoxysklerol 3% SCL or 3 × RBL. The primary outcome measures are symptom reduction by means of PROMs, recurrence and complication rates. Secondary outcome measures are patient experience, number of treatments and days of sick leave from work. Data are collected at 4 different time points. DISCUSSION: The THROS trial is the first large multicentre randomised trial to study the difference in effectivity between RBL and SCL for the treatment of grade 1-2 HD. It will provide information as to which treatment method (RBL or SCL) is the most effective, gives fewer complications and is experienced by the patient as the best option. ETHICS AND DISSEMINATION: The study protocol has been approved by the Medical Ethics Review Committee of the Amsterdam University Medical Centers, location AMC (nr. 2020_053). The gathered data and results will be submitted for publication in peer-reviewed journals and spread to coloproctological associations and guidelines. TRIAL REGISTRATION: Dutch Trial Register NL8377 . Registered on 12-02-2020.

Purpose First, to assess the number of spinal cord anomalies (SCA), specifically tethered spinal cord (TSC) in patients with anorectal malformations (ARM), identified with spinal cord imaging (i.e. spinal cord US and/or MRI). Second, to report outcomes after TSC treatment. Methods A retrospective mono-center study was performed. All ARM patients born between January 2000 and December 2021 were included. Screening for SCA consisted of spinal cord US and/or MRI. Radiology reports were scored on presence of SCA. Data were presented with descriptive statistics. Results In total, 254 patients were eligible for inclusion, of whom 234 (92.1%) underwent spinal cord imaging. In total, 52 (22.2%) patients had a SCA, diagnosed with US (n = 20, 38.5%), MRI (n = 10, 19.2%), or both US and MRI (n = 22, 42.3%), of whom 12 (23.5%) with simple, 27 (52.7%) intermediate, and 12 (23.5%) complex ARM types. TSC was identified in 19 patients (8.1%), of whom 4 (21.1%) underwent uncomplicated neurosurgical intervention. Conclusions SCA were present in 22% of ARM patients both in simple, as well as more complex ARM types. TSC was present in 19 patients with SCA, of whom 4 underwent uncomplicated neurosurgical intervention. Therefore, screening for SCA seems to be important for all ARM patients, regardless of ARM type. Level of Evidence Level III.

Background Monocytes -key regulators of the innate immune response- are actively involved in the pathogenesis of systemic lupus erythematosus (SLE). We sought to identify novel compounds that might serve as monocyte-directed targeted therapies in SLE. Results We performed mRNA sequencing in monocytes from 15 patients with active SLE and 10 healthy individuals. Disease activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Leveraging the drug repurposing platforms iLINCS, CLUE and L1000CDS2, we identified perturbagens capable of reversing the SLE monocyte signature. We identified transcription factors and microRNAs (miRNAs) that regulate the transcriptome of SLE monocytes, using the TRRUST and miRWalk databases, respectively. A gene regulatory network, integrating implicated transcription factors and miRNAs was constructed, and drugs targeting central components of the network were retrieved from the DGIDb database. Inhibitors of the NF-κB pathway, compounds targeting the heat shock protein 90 (HSP90), as well as a small molecule disrupting the Pim-1/NFATc1/NLRP3 signaling axis were predicted to efficiently counteract the aberrant monocyte gene signature in SLE. An additional analysis was conducted, to enhance the specificity of our drug repurposing approach on monocytes, using the iLINCS, CLUE and L1000CDS2 platforms on publicly available datasets from circulating B-lymphocytes, CD4+ and CD8+ T-cells, derived from SLE patients. Through this approach we identified, small molecule compounds, that could potentially affect more selectively the transcriptome of SLE monocytes, such as, certain NF-κB pathway inhibitors, Pim-1 and SYK kinase inhibitors. Furthermore, according to our network-based drug repurposing approach, an IL-12/23 inhibitor and an EGFR inhibitor may represent potential drug candidates in SLE. Conclusions Application of two independent - a transcriptome-reversal and a network-based -drug repurposing strategies uncovered novel agents that might remedy transcriptional disturbances of monocytes in SLE.

Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. Methods This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. Discussion The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. Trial registration number The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL).

Background Despite increasing use of continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII, insulin pumps) in type 1 diabetes (T1D) in pregnancy, achieving recommended pregnancy glycaemic targets (3.5–7.8 mmol/L or 63–140 mg/dL) remains challenging. Consequently, the risk of adverse pregnancy outcomes remains high. Outside pregnancy, hybrid closed-loop (HCL) insulin delivery systems have led to a paradigm shift in the management of T1D, with 12% higher time in glucose target range (TIR) compared to conventional CSII. However, most commercially available HCL systems are currently not approved for use in pregnancy. This study aims to evaluate the efficacy, safety and cost-effectiveness of the MiniMed™ 780G HCL system (Medtronic) in T1D in pregnancy. Methods In this international, open-label, randomized controlled trial (RCT), we will compare the MiniMed™ 780G HCL system to standard of care (SoC) in T1D in pregnancy. Women aged 18–45 years with T1D diagnosis of at least one year, HbA1c ≤ 86 mmol/mol (≤ 10%), and confirmed singleton pregnancy up to 11 weeks 6 days will be eligible. After providing written informed consent, all participants will wear a similar CGM system (Guardian™ 3 or Guardian™ 4 CGM) during a 10-day run-in phase. After the run-in phase, participants will be randomised 1:1 to 780G HCL (intervention) or SoC [control, continuation of current T1D treatment with multiple daily injections (MDI) or CSII and any type of CGM] stratified according to centre, baseline HbA1c ( Discussion This large RCT will evaluate a widely used commercially available HCL system in T1D in pregnancy. Recruitment began in January 2021 and was completed in October 2022. Study completion is expected in May 2023. Trial registration ClinicalTrials.gov: NCT04520971. Registration date: August 20, 2020. https://clinicaltrials.gov/ct2/show/NCT04520971

Background: Primary carnitine deficiency is an inborn error of metabolism, which can lead to life-threating complications early in life. Low carnitine levels can be detected by newborn bloodspot screening (NBS). However, NBS can also identify, mostly asymptomatic, mothers with primary carnitine deficiency. To identify mothers’ needs and areas for improving screening practice, this study explored the experiences with, and opinions on primary carnitine deficiency screening in NBS among women diagnosed through NBS of their newborn. Methods: Twelve Dutch women were interviewed, 3–11 years after diagnosis. Data were analysed using a thematic approach. Results: Four main themes were derived: 1) psychological impact of primary carnitine deficiency diagnosis, 2) becoming a patient and “patient-in-waiting”, 3) information issues and care provision, and 4) primary carnitine deficiency as part of the NBS panel. Mothers shared that they did not experience major psychological distress of the diagnosis. They did experience (recall) various emotions following the initial abnormal NBS result, including fear and anxiety as well as relief, and emotions regarding their own diagnosis, including uncertainty about health risks and treatment effectiveness. Some felt a patient-in-waiting. Many participants experienced a lack of information, especially shortly after receiving the abnormal NBS result. All shared the belief that screening for primary carnitine deficiency in NBS is beneficial for the newborn, and, given the information they received, also considered the knowledge beneficial for their own health. Conclusions: Psychological burden following diagnosis was experienced by women as limited, although the experienced lack of information amplified feelings of uncertainty and anxiety. Most mothers believed that benefits of knowing about primary carnitine deficiency outweighed the disadvantages. Mothers’ perspectives should be incorporated in policy-making about primary carnitine deficiency in NBS.

Background: This study aimed to assess the feasibility of postmortem ultra-high-field magnetic resonance imaging (UHF-MRI) to study fetal musculoskeletal anatomy and explore the contribution of variation in iodine and formaldehyde (paraformaldehyde, PFA) treatment of tissue. Methods: Seven upper extremities from human fetuses with gestational ages of 19 to 24 weeks were included in this experimental study, approved by the Medical Research Ethics Committee. The specimens were treated with various storage (0.2–4% PFA) and staining (Lugol’s solution) protocols and the wrist joint was subsequently imaged with 7.0 T UHF-MRI. Soft-tissue contrast was quantified by determining regions of interest within a chondrified carpal bone (CCB) from the proximal row, the triangular fibrocartilage (TFC), and the pronator quadratus muscle (PQM) and calculating the contrast ratios (CRs) between mean signal intensities of CCB to TFC and CCB to PQM. Results: UHF-MRI showed excellent soft-tissue contrast in different musculoskeletal tissues. Increasing storage time in 4% PFA, CRs decreased, resulting in a shift from relatively hyperintense to hypointense identification of the CCB. Storage in 0.2% PFA barely influenced the CRs over time. Lugol’s solution caused an increase in CRs and might have even contributed to the inversion of the CRs. Conclusions: UHF-MRI is a feasible technique to image musculoskeletal structures in fetal upper extremities and most successful after short storage in 4% PFA or prolonged storage in 0.2% PFA. The use of Lugol’s solution is not detrimental on soft-tissue MRI contrast and therefore enables effectively combining UHF-MRI with contrast-enhanced micro-computed tomography using a single preparation of the specimen. Relevance statement: UHF-MRI can be performed after CE-micro-CT to take advantage of both techniques. Key points: • UHF-MRI is feasible to study human fetal cartilaginous and ligamentous anatomy. • Storage in low PFA concentrations (i.e., 0.2%) improves soft-tissue contrast in UHF-MRI. • Limited preservation time in high concentrations of PFA improves soft-tissue contrast in UHF-MRI. • Prior staining with Lugol’s solution does not reduce soft-tissue contrast in UHF-MRI. Graphical Abstract: [Figure not available: see fulltext.].

Prior models have been developed to predict survival for patients with esophagogastric cancer undergoing curative treatment or first-line chemotherapy (SOURCE models). Comprehensive clinical prediction models for patients with esophagogastric cancer who will receive second-line chemotherapy or best supportive care are currently lacking. The aim of our study was to develop and internally validate a new clinical prediction model, called SOURCE beyond first-line, for survival of patients with metastatic esophagogastric adenocarcinoma after failure of first-line palliative systemic therapy. Patients with unresectable or metastatic esophageal or gastric adenocarcinoma (2015-2017) who received first-line systemic therapy (N = 1067) were selected from the Netherlands Cancer Registry. Patient, tumor and treatment characteristics at primary diagnosis and at progression of disease were used to develop the model. A Cox proportional hazards regression model was developed through forward and backward selection using Akaike's Information Criterion. The model was internally validated through 10-fold cross-validations to assess performance. Model discrimination (C-index) and calibration (slope and intercept) were used to evaluate performance of the complete and cross-validated models. The final model consisted of 11 patient tumor and treatment characteristics. The C-index was 0.75 (0.73-0.78), calibration slope 1.01 (1.00-1.01) and calibration intercept 0.01 (0.01-0.02). Internal cross-validation of the model showed that the model performed adequately on unseen data: C-index was 0.79 (0.77-0.82), calibration slope 0.93 (0.85-1.01) and calibration intercept 0.02 (-0.01 to 0.06). The SOURCE beyond first-line model predicted survival with fair discriminatory ability and good calibration.

The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage.

Background: malnutrition represents a key priority for global health policy, yet the impact of nutritional state on cancer surgery worldwide remains poorly described. We aimed to analyse the effect of malnutrition on early postoperative outcomes following elective surgery for colorectal or gastric cancer. Methods: we did an international, multicentre, prospective cohort study of patients undergoing elective surgery for colorectal or gastric cancer between April 1, 2018, and Jan 31, 2019. Patients were excluded if the primary pathology was benign, they presented with cancer recurrence, or if they underwent emergency surgery (within 72 h of hospital admission). Malnutrition was defined with the Global Leadership Initiative on Malnutrition criteria. The primary outcome was death or a major complication within 30 days of surgery. Multilevel logistic regression and a three-way mediation analysis were done to establish the relationship between country income group, nutritional status, and 30-day postoperative outcomes. Findings: this study included 5709 patients (4593 with colorectal cancer and 1116 with gastric cancer) from 381 hospitals in 75 countries. The mean age was 64·8 years (SD 13·5) and 2432 (42·6%) patients were female. Severe malnutrition was present in 1899 (33·3%) of 5709 patients, with a disproportionate burden in upper-middle-income countries (504 [44·4%] of 1135) and low-income and lower-middle-income countries (601 [62·5%] of 962). After adjustment for patient and hospital risk factors, severe malnutrition was associated with an increased risk of 30-day mortality across all country income groups (high income: adjusted odds ratio [aOR] 1·96 [95% CI 1·14–3·37], p=0·015; upper-middle income: 3·05 [1·45–6·42], p=0·003; low income and lower-middle income: 11·57 [5·87–22·80], p

BACKGROUND: The use of a simultaneous resection (SIMR) in patients with synchronous colorectal liver metastases (sCRLM) has increased over the past decades. However, it remains unclear when a SIMR is beneficial and when it should be avoided. The aim of this retrospective cohort study was therefore to compare the outcomes of a SIMR for sCRLM in different settings, and to assess which factors are independently associated with unfavorable outcomes.METHODS: To perform this retrospective cohort study, patients with sCRLM undergoing SIMR (2004-2019) were extracted from an international multicenter database, and their outcomes were compared after stratification according to the type of liver and colorectal resection performed. Factors associated with unfavorable outcomes were identified through multivariable logistic regression.RESULTS: Overall, 766 patients were included, encompassing colorectal resections combined with a major liver resection (n=122), minor liver resection in the anterolateral (n=407), or posterosuperior segments ('Technically major', n=237). Minor and technically major resections, compared to major resections, were more often combined with a rectal resection (29.2 and 36.7 vs. 20.5%, respectively, both P=0.003) and performed fully laparoscopic (22.9 and 23.2 vs. 6.6%, respectively, both P = 0.003). Major and technically major resections, compared to minor resections, were more often associated with intraoperative transfusions (42.9 and 38.8 vs. 20%, respectively, both P = 0.003) and unfavorable incidents (9.6 and 9.8 vs. 3.3%, respectively, both P≤0.063). Major resections were associated, compared to minor and technically major resections, with a higher overall morbidity rate (64.8 vs. 50.4 and 49.4%, respectively, both P≤0.024) and a longer length of stay (12 vs. 10 days, both P≤0.042). American Society of Anesthesiologists grades ≥3 [adjusted odds ratio (aOR): 1.671, P=0.015] and undergoing a major liver resection (aOR: 1.788, P=0.047) were independently associated with an increased risk of severe morbidity, while undergoing a left-sided colectomy was associated with a decreased risk (aOR: 0.574, P=0.013).CONCLUSIONS: SIMR should primarily be reserved for sCRLM patients in whom a minor or technically major liver resection would suffice and those requiring a left-sided colectomy. These findings should be confirmed by randomized studies comparing SIMR with staged resections.

BACKGROUND AND AIMS: The DRAINAGE trial was a randomized controlled trial comparing preoperative endoscopic (EBD) and percutaneous biliary drainage (PTBD) in patients with potentially resectable, perihilar cholangiocarcinoma (pCCA). The aim of this study was to compare the long-term outcomes.METHODS: Patients were randomized in four tertiary referral centers. Follow-up data were available for all included patients. Primary outcome was overall survival (OS). Secondary outcomes were readmissions, and re-interventions not including in-trial interventions.RESULTS: A total of 54 patients were randomized; 27 in both groups. Median follow-up for both groups was 62 months (95% CI 54-70). The median OS was 13 months (95% CI 7.9-18.1) in the EBD and 7 months (95% CI 0.0-17.2) in the PTBD group (P = 0.28). Twenty (37%, n = 8 EBD vs n = 12 PTBD, P = 0.43) of 54 patients were readmitted at least once, mostly due to drainage-related complications (n = 13, 24%). Of note, 14 out of the 54 patients died within the trial. A total of 76 drainage procedures (32 EBD and 44 PTBD) were performed in 28 patients. The median number of stent or drain placements was 2 (2-4) for the EBD group and 2 (1-3) for the PTBD group (P = 0.77).DISCUSSION: Although this follow-up study represented a small cohort, no long-term differences in survival, readmissions, and drainage procedures for EBD and PTBD were found, even when comparing the resected and unresected group. However, this study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA, even in tertiary referral centers.

BACKGROUND Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING Swiss Cancer Research foundation.

Purpose: Total elbow arthroplasty (TEA) is rarely performed compared to other arthroplasties. For many surgical procedures, literature shows better outcomes when they are performed by experienced surgeons and in so-called ‘high-volume’ hospitals. We systematically reviewed the literature on the relationship between surgical volume and outcomes following TEA. Methods: A literature search was performed using the MEDLINE, EMBASE and CINAHL databases. The literature was systematically reviewed for original studies comparing TEA outcomes among hospitals or surgeons with different annual or career volumes. For each study, data were collected on study design, indications for TEA, number of included patients, implant types, cut-off values for volume, number and types of complications, revision rate and functional outcome measures. The methodological quality of the included studies was assessed using the Newcastle–Ottawa Scale. Results: Two studies, which included a combined 2301 TEAs, found that higher surgeon volumes were associated with lower revision rates. The examined complication rates did not differ between high- and low-volume surgeons. In one study, low-hospital volume is associated with an increased risk of revision compared to high-volume hospitals, but for other complication types, no difference was found. Conclusions: Based on the results, the evidence suggests that high-volume centers have a lower revision rate in the long term. No minimum amount of procedures per year can be advised, as the included studies have different cut-off values between groups. As higher surgeon- and center-volume, (therefore presumably experience) appear to yield better outcomes, centralization of total elbow arthroplasty should be encouraged.

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.

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Background: Increasing evidence suggests that appendicectomy as alternative treatment for ulcerative colitis (UC), especially in patients with histopathological appendiceal inflammation. Intestinal ultrasound (IUS) is a non-invasive diagnostic modality to characterise appendiceal inflammation. Aims: To assess appendiceal IUS characteristics in UC patients and compare findings to healthy controls (HC). Methods: In this prospective study, appendiceal IUS was performed in consecutive UC patients with active (A; n = 35) or quiescent (Q; n = 30) disease and in HC (n = 30). Transverse appendiceal diameter (TAD) and additional IUS parameters (bowel wall thickness, submucosal layer thickness and colour Doppler signal) were assessed. Results: The appendix was visualised in 41/65 UC patients (63.1%; A vs. Q: 23/35 vs. 18/30, p = 0.67) and 18/30 (60%) HC. UC patients had a higher TAD (A: 5.5 mm, Q: 5.0 mm, HC: 4.3 mm; A-HC p < 0.01; Q-HC p = 0.01, A-Q p = ns) and submucosal layer thickness (A: 1.0 mm, Q: 1.0 mm, HC: 0.7 mm; A-HC p < 0.01, Q-HC: p = 0.01, A-Q: p = ns) when compared to HC. A TAD ≥6 mm corresponding to an ultrasonographic suspicion of acute appendicitis was mainly reported in A-UC patients (A: 43%; Q: 6%; HC: 0%, p = 0.01) and occurred irrespective of disease extent. However, none of the patients had a clinical suspicion of acute appendicitis. Conclusion: A TAD ≥6 mm was predominantly seen in A-UC. TAD was higher in UC patients compared to HC irrespective of disease activity and was characterised by an increased submucosal layer thickness. IUS therefore has the potential to identify UC patients with appendiceal inflammation.

Objectives In patients with rectal cancer, the size and location of lateral lymph nodes (LLNs) are correlated to increased lateral local recurrence rates. Sufficient knowledge and accuracy when measuring these features are therefore essential. The objective of this study was to evaluate the variation in measurements and anatomical classifications of LLNs before and after training. Methods Fifty-three Dutch radiologists examined three rectal MRI scans and completed a questionnaire. Presence, location, size, and suspiciousness of LLNs were reported. This assessment was repeated after a 2-hour online training by the same radiologists with the same three cases plus three additional cases. Three expert radiologists independently evaluated these 6 cases and served as the standard of reference. Results Correct identification of the anatomical location improved in case 1 (62 to 77% (p = .077)) and in case 2 (46 to 72% (p = .007)) but decreased in case 3 (92 to 74%, p = .453). Compared to the first three cases, cases 4, 5, and 6 all had a higher initial consensus of 73%, 79%, and 85%, respectively. The mean absolute deviation of the short-axis measurements in cases 1–3 were closer—though not significantly—to the expert reference value after training with reduced ranges and standard deviations. Subjective determination of malignancy had a high consensus rate between participants and experts. Conclusion Though finding a high consensus rate for determining malignancy of LLNs, variation in short-axis measurements and anatomical location classifications were present and improved after training. Adequate training would support the challenges involved in evaluating LLNs appropriately. Key Points • Variation was present in the assessment of the anatomical location and short-axis size of lateral lymph nodes. • In certain cases, the accuracy of short-axis measurements and anatomical location, when compared to an expert reference value, improved after a training session. • Consensus before and after training on whether an LLN was subjectively considered to be suspicious for malignancy was high.

Physical exercise training has been positioned as a behavioral strategy to prevent or alleviate obesity via promotion of energy expenditure as well as modulation of energy intake resulting from changes in dietary preference. Brain adaptations underlying the latter process are incompletely understood. Voluntary wheel running (VWR) is a self-reinforcing rodent paradigm that mimics aspects of human physical exercise training. Behavioral and mechanistic insight from such fundamental studies can help optimize therapies that improve body weight and metabolic health based on physical exercise training in humans. To assess the effects of VWR on dietary self-selection, male Wistar rats were given access to a two-component "no-choice" control diet (CD; consisting of prefabricated nutritionally complete pellets and a bottle with tap water) or a four-component free-choice high-fat high-sucrose diet (fc-HFHSD; consisting of a container with prefabricated nutritionally complete pellets, a dish with beef tallow, a bottle with tap water, and a bottle with 30% sucrose solution). Metabolic parameters and baseline dietary self-selection behavior during sedentary (SED) housing were measured for 21 days, after which half of the animals were allowed to run on a vertical running wheel (VWR) for another 30 days. This resulted in four experimental groups (SEDCD, SEDfc-HFHSD, VWRCD, and VWRfc-HFHSD). Gene expression of opioid and dopamine neurotransmission components, which are associated with dietary self-selection, was assessed in the lateral hypothalamus (LH) and nucleus accumbens (NAc), two brain regions involved in reward-related behavior, following 51 and 30 days of diet consumption and VWR, respectively. Compared to CD controls, consumption of fc-HFHSD before and during VWR did not alter total running distances. VWR and fc-HFHSD had opposite effects on body weight gain and terminal fat mass. VWR transiently lowered caloric intake and increased and decreased terminal adrenal and thymus mass, respectively, independent of diet. VWR during fc-HFHSD consumption consistently increased CD self-selection, had an acute negative effect on fat self-selection, and a delayed negative effect on sucrose solution self-selection compared to SED controls. Gene expression of opioid and dopamine neurotransmission components in LH and NAc were unaltered by fc-HFHSD or VWR. We conclude that VWR modulates fc-HFHSD component self-selection in a time-dependent manner in male Wistar rats.

Background Numerous prediction models estimating the risk of complications after esophagectomy exist but are rarely used in practice. The aim of this study was to compare the clinical judgment of surgeons using these prediction models. Methods Patients with resectable esophageal cancer who underwent an esophagectomy were included in this prospective study. Prediction models for postoperative complications after esophagectomy were selected by a systematic literature search. Clinical judgment was given by three surgeons, indicating their estimated risk for postoperative complications in percentage categories. The best performing prediction model was compared with the judgment of the surgeons, using the net reclassification improvement (NRI), category-free NRI (cfNRI), and integrated discrimination improvement (IDI) indexes. Results Overall, 159 patients were included between March 2019 and July 2021, of whom 88 patients (55%) developed a complication. The best performing prediction model showed an area under the receiver operating characteristic curve (AUC) of 0.56. The three surgeons had an AUC of 0.53, 0.55, and 0.59, respectively, and all surgeons showed negative percentages of cfNRIevents and IDIevents, and positive percentages of cfNRInonevents and IDIevents. This indicates that in the group of patients with postoperative complications, the prediction model performed better, whereas in the group of patients without postoperative complications, the surgeons performed better. NRIoverall was 18% for one surgeon, while the remainder of the NRIoverall, cfNRIoverall and IDIoverall scores showed small differences between surgeons and the prediction models. Conclusion Prediction models tend to overestimate the risk of any complication, whereas surgeons tend to underestimate this risk. Overall, surgeons’ estimations differ between surgeons and vary between similar to slightly better than the prediction models.

Endothelial cells (ECs) form a precisely regulated polarized monolayer in capillary walls. Vascular endothelial growth factor-A (VEGF-A) induces endothelial hyperpermeability, and VEGF-A applied to the basolateral side, but not the apical side, has been shown to be a strong barrier disruptor in blood–retinal barrier ECs. We show here that VEGF-A presented to the basolateral side of human umbilical vein ECs (HUVECs) induces higher permeability than apical stimulation, which is similar to results obtained with bovine retinal ECs. We investigated with immunocytochemistry and confocal imaging the distribution of VEGF receptor-2 (VEGFR2) and neuropilin-2 (NRP2) in perinuclear apical and basolateral membrane domains. Orthogonal z-sections of cultured HUVECs were obtained, and the fluorescence intensity at the apical and basolateral membrane compartments was measured. We found that VEGFR2 and NRP2 are evenly distributed throughout perinuclear apical and basolateral membrane compartments in unstimulated HUVECs grown on Transwell inserts, whereas basolateral VEGF-A stimulation induces a shift toward basolateral VEGFR2 and NRP2 localization. When HUVECs were grown on coverslips, the distribution of VEGFR2 and NRP2 across the perinuclear apical and basolateral membrane domains was different. Our findings demonstrate that HUVECs dynamically regulate VEGFR2 and NRP2 localization on membrane microdomains, depending on growth conditions and the polarity of VEGF-A stimulation.

Background: Concomitant use of P-glycoprotein inhibitors can reduce clearance of edoxaban and increase its plasma concentration. Caution is advised with simultaneous use of edoxaban and the frequently used P-glycoprotein inhibitor tamoxifen. However, pharmacokinetic data are lacking. Objectives: This study aimed to assess the effect of tamoxifen on edoxaban clearance. Methods: This was a prospective, self-controlled, pharmacokinetic study in breast cancer participants starting tamoxifen. Edoxaban was given at a dose of 60 mg once daily for 4 consecutive days, first without tamoxifen and later with concomitant tamoxifen in steady-state. On day 4 of both edoxaban sequences, serial blood samples were taken. A population pharmacokinetic model was developed using nonlinear mixed effects modelling in which the effect of tamoxifen on edoxaban clearance was assessed. Additionally, mean area under the curves (AUC) were estimated. Geometric least square means (GLM) ratios were calculated and no interaction was concluded if the 90 % CI was within the 80–125 % no-effect boundaries. Results: Twenty-four women with breast cancer scheduled for tamoxifen were included. The median age was 56 years (IQR 51–63). The average edoxaban clearance was 32.0 L/h (95 % CI, 11.1–35.0 L/h). There was no effect of tamoxifen on edoxaban clearance, with a fraction of 100 % (95 % CI 92–108) compared to clearance without tamoxifen. The mean AUCs were 1923 ng*h/ml (SD 695) without tamoxifen and 1947 ng*h/ml (SD 595) with tamoxifen (GLM-ratio 100.4; 90 % CI 98.6–102.2). Conclusions: Concomitant use of the P-glycoprotein inhibitor tamoxifen does not lead to reduced clearance of edoxaban in patients with breast cancer.

References 3 and 9 are duplicates (identical); hence, one was deleted and the references including their citations in the text were renumbered accordingly. The original article has been corrected.

BACKGROUND: Although curative treatment options are identical for male and female gastroesophageal cancer patients, access to care and survival may vary. This study aimed to compare treatment allocation and survival between male and female patients with potentially curable gastroesophageal cancer.; METHODS: Nationwide cohort study including all patients with potentially curable gastroesophageal squamous cell or adenocarcinoma diagnosed between 2006 and 2018 registered in the Netherlands Cancer Registry. The main outcome, treatment allocation, was compared between male and female patients with oesophageal adenocarcinoma (EAC), oesophageal squamous cell carcinoma (ESCC), and gastric adenocarcinoma (GAC). Additionally, 5-year relative survival with relative excess risk (RER), that is, adjusted for the normal life expectancy, was compared.; RESULTS: Among 27,496 patients (68.8% men), most were allocated to curative treatment (62.8%), although rates dropped to 45.6%>70 years. Curative treatment rates were comparable among younger male and female patients (≤70 years) with gastroesophageal adenocarcinoma, while older females with EAC were less frequently allocated to curative treatment than males (OR=0.85, 95%confidence interval [CI] 0.73-0.99). For those allocated to curative treatment, relative survival was superior for female patients with EAC (RER=0.88, 95%CI 0.80-0.96) and ESCC (RER=0.82, 95%CI 0.75-0.91), and comparable for males and females with GAC (RER=1.02, 95%CI 0.94-1.11).; CONCLUSIONS: While curative treatment rates were comparable between younger male and female patients with gastroesophageal adenocarcinoma, treatment disparities were present between older patients. When treated, the survival of females with EAC and ESCC was superior to males. The treatment and survival gaps between male and female patients with gastroesophageal cancer warrant further exploration and could potentially improve treatment strategies and survival. Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Introduction and objective: The Dutch university medical centres (UMC's) are on the forefront when it comes to validation, implementation and research of telemonitoring. To aid the UMC's in their effort, the Dutch Government has supported the UMC's by fostering the ‘Citrien eHealth program’. This program aims at nationwide implementation and upscaling of telemonitoring via a collaborative network. To quantify the success of this program, this study aims to provide insights into the current adoption of telemonitoring by health care professionals (HCP) within Dutch UMC's. Methods: Based on the evaluation framework as adapted from the Normalization Process Theory (NPT) a cross-sectional study was conducted in all Dutch UMC's. Thirty healthcare professionals (HCPs) per UMC were invited to complete the 23-item Normalization MeAsure Development (NoMAD) questionnaire, a tool to assess the degree of normalisation of telemonitoring. Results: The over-all response rate was 52.4% (124/240). Over 80% of respondents agreed or strongly agreed that they understand how telemonitoring affects the nature of their work, with a mean score of 1.49 (N = 117, SD 0.74). HCPs reported to believe telemonitoring will become a normal part of their work in the near future (N = 124, mean = 8.67, SD = 1.38). Using the Wilcoxon signed-rank test, the difference between current practise and future use of telemonitoring predicts to be statistically significant (Z = − 7.505, p ≤ 0.001). Mean scores for appropriate training and sufficient resources are relatively low (2.39 and 2.70 respectively), indicating a barrier for collective action. Conclusion: This is the first study to assess the implementation of telemonitoring as standard practise across Dutch UMCs. The HCPs in this study are the frontrunners, believing that telemonitoring will become standard practise in the future despite the fact that it is currently not. Based on the results of this study, both educational and implementation strategies including practical skills training are highly recommended in order to scale up telemonitoring widely.