AZ Groeninge

OBJECTIVE: The European Guidelines Meeting on Laparoscopic Liver Surgery was held in Southampton on February 10 and 11, 2017 with the aim of presenting and validating clinical practice guidelines for laparoscopic liver surgery. BACKGROUND: The exponential growth of laparoscopic liver surgery in recent years mandates the development of clinical practice guidelines to direct the speciality's continued safe progression and dissemination. METHODS: A unique approach to the development of clinical guidelines was adopted. Three well-validated methods were integrated: the Scottish Intercollegiate Guidelines Network methodology for the assessment of evidence and development of guideline statements; the Delphi method of establishing expert consensus, and the AGREE II-GRS Instrument for the assessment of the methodological quality and external validation of the final statements. RESULTS: Along with the committee chairman, 22 European experts; 7 junior experts and an independent validation committee of 11 international surgeons produced 67 guideline statements for the safe progression and dissemination of laparoscopic liver surgery. Each of the statements reached at least a 95% consensus among the experts and were endorsed by the independent validation committee. CONCLUSION: The European Guidelines Meeting for Laparoscopic Liver Surgery has produced a set of clinical practice guidelines that have been independently validated for the safe development and progression of laparoscopic liver surgery. The Southampton Guidelines have amalgamated the available evidence and a wealth of experts' knowledge taking in consideration the relevant stakeholders' opinions and complying with the international methodology standards.

BACKGROUND: As the natural healing capacity of damaged articular cartilage is poor, joint surface injuries are a prime target for regenerative medicine. Characterized chondrocyte implantation uses an autologous cartilage cell therapy product that has been optimized for its biological potency to form stable cartilage tissue in vivo. PURPOSE: To determine whether, in symptomatic cartilage defects of the femoral condyle, structural regeneration with characterized chondrocyte implantation is superior to repair with microfracture. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Characterized chondrocyte implantation was compared with microfracture in patients with single grade III to IV symptomatic cartilage defects of the femoral condyles in a multicenter trial. Patients aged 18 to 50 years were randomized to characterized chondrocyte implantation (n = 57) or microfracture (n = 61). Structural repair was blindly assessed in biopsy specimens taken at 1 year using (1) computerized histomorphometry and (2) evaluation of overall histological components of structural repair. Clinical outcome was measured using the self administered Knee injury and Osteoarthritis Outcome Score. Adverse events were recorded throughout the study. RESULTS: Characterized chondrocyte implantation resulted in better structural repair, as assessed by histomorphometry (P = .003) and overall histologic evaluation (P = .012). Aspects of structural repair relating to chondrocyte phenotype and tissue structure were superior with characterized chondrocyte implantation. Clinical outcome as measured by the Knee injury and Osteoarthritis Outcome Score at 12 to 18 months after characterized chondrocyte implantation was comparable with microfracture at this stage. Both treatment groups had a similar mean baseline overall Knee injury and Osteoarthritis Outcome Score (56.30 +/- 13.61 and 59.53 +/- 14.95 for microfracture and characterized chondrocyte implantation, respectively), which increased in both groups to 70.56 +/- 12.39 and 72.63 +/- 15.55 at 6 months, 73.26 +/- 14.66 and 73.10 +/- 16.01 at 12 months, and 74.73 +/- 17.01 and 75.04 +/- 14.50 at 18 months, respectively. Both techniques were generally well tolerated; the incidence of adverse events after characterized chondrocyte implantation was not markedly increased compared with that for microfracture. CONCLUSION: One year after treatment, characterized chondrocyte implantation was associated with a tissue regenerate that was superior to that after microfracture. Short-term clinical outcome was similar for both treatments. The superior structural outcome may result in improved long-term clinical benefit with characterized chondrocyte implantation. Long-term follow-up is needed to confirm these findings.

BACKGROUND: Recognizing the rapidly increasing interest and evidence in using metastasis-directed radiotherapy (MDRT) for oligometastatic disease (OMD), ESTRO and ASTRO convened a committee to establish consensus regarding definitions of OMD and define gaps in current evidence. METHODS: A systematic literature review focused on curative intent MDRT was performed in Medline, Embase and Cochrane. Subsequent consensus opinion, using a Delphi process, highlighted the current state of evidence and the limitations in the available literature. RESULTS: Available evidence regarding the use of MDRT for OMD mostly derives from retrospective, single-centre series, with significant heterogeneity in patient inclusion criteria, definition of OMD, and outcomes reported. Consensus was reached that OMD is largely independent of primary tumour, metastatic location and the presence or length of a disease-free interval, supporting both synchronous and metachronous OMD. In the absence of clinical data supporting a maximum number of metastases and organs to define OMD, and of validated molecular biomarkers, consensus supported the ability to deliver safe and clinically meaningful radiotherapy with curative intent to all metastatic sites as a minimum requirement for defining OMD in the context of radiotherapy. Systemic therapy induced OMD was identified as a distinct state of OMD. High-resolution imaging to assess and confirm OMD is crucial, including brain imaging when indicated. Minimum common endpoints such as progression-free and overall survival, local control, toxicity and quality-of-life should be reported; uncommon endpoints as deferral of systemic therapy and cost were endorsed. CONCLUSION: While significant heterogeneity exists in the current OMD definitions in the literature, consensus was reached on multiple key questions. Based on available data, OMD can to date be defined as 1-5 metastatic lesions, a controlled primary tumor being optional, but where all metastatic sites must be safely treatable. Consistent definitions and reporting are warranted and encouraged in ongoing trials and reports generating further evidence to optimize patient benefits.

Imatinib mesylate (imatinib) has been shown to be highly efficacious in the treatment of chronic myeloid leukemia (CML). Continuous and adequate dosing is essential for optimal outcomes and with imatinib treatment possibly being lifelong, patient adherence is critical. The ADAGIO (Adherence Assessment with Glivec: Indicators and Outcomes) study aimed to assess prospectively over a 90-day period the prevalence of imatinib nonadherence in patients with CML; to develop a multivariate canonical correlation model of how various determinants may be associated with various measures of nonadherence; and to examine whether treatment response is associated with adherence levels. A total of 202 patients were recruited from 34 centers in Belgium, of whom 169 were evaluable. One-third of patients were considered to be nonadherent. Only 14.2% of patients were perfectly adherent with 100% of prescribed imatinib taken. On average, patients with suboptimal response had significantly higher mean percentages of imatinib not taken (23.2%, standard deviation [SD] = 23.8) than did those with optimal response (7.3%, SD = 19.3, P = .005; percentages calculated as proportions x 100). Nonadherence is more prevalent than patients, physicians, and family members believe it is, and therefore should be assessed routinely. It is associated with poorer response to imatinib. Several determinants may serve as alert signals, many of which are clinically modifiable.

OBJECTIVE: Neutrophil extracellular traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular, no information is yet available on the presence of NETs in cerebral occlusions. Such information is, however, essential to improve current thrombolytic therapy with tissue plasminogen activator (t-PA). This study aimed at investigating the presence of neutrophils and more specifically NETs in ischemic stroke thrombi. METHODS: Sixty-eight thrombi retrieved from ischemic stroke patients undergoing endovascular treatment were characterized by immunostaining using neutrophil markers (CD66b and neutrophil elastase) and NET markers (citrullinated histone H3 [H3Cit] and extracellular DNA). Neutrophils and NETs were quantified. In addition, extracellular DNA was targeted by performing ex vivo lysis of retrieved thrombi with DNase 1 and t-PA. RESULTS: Neutrophils were detected extensively throughout all thrombi. H3Cit, a hallmark of NETs, was observed in almost all thrombi. H3Cit-positive area varied up to 13.45% of total thrombus area. Colocalization of H3Cit with extracellular DNA released from neutrophils confirmed the specific presence of NETs. H3Cit was more abundant in thrombi of cardioembolic origin compared to other etiologies. Older thrombi contained significantly more neutrophils and H3Cit compared to fresh thrombi. Interestingly, ex vivo lysis of patient thrombi was more successful when adding DNase 1 to standard t-PA. INTERPRETATION: Neutrophils and NETs form important constituents of cerebral thrombi. Targeting of NETs with DNase 1 might have prothrombolytic potential in treatment of acute ischemic stroke. Ann Neurol 2017;82:223-232.

BACKGROUND: Glomerular filtration rate (GFR) is accepted as the best indicator of kidney function and is commonly estimated from serum creatinine (SCr)-based equations. Separate equations have been developed for children (Schwartz equation), younger and middle-age adults [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation] and older adults [Berlin Initiative Study 1 (BIS1) equation], and these equations lack continuity with ageing. We developed and validated an equation for estimating the glomerular filtration rate that can be used across the full age spectrum (FAS). METHODS: The new FAS equation is based on normalized serum creatinine (SCr/Q), where Q is the median SCr from healthy populations to account for age and sex. Coefficients for the equation are mathematically obtained by requiring continuity during the paediatric-adult and adult-elderly transition. Research studies containing a total of 6870 healthy and kidney-diseased white individuals, including 735 children, <18 years of age, 4371 adults, between 18 and 70 years of age, and 1764 older adults, ≥70 years of age with measured GFR (inulin, iohexol and iothalamate clearance) and isotope dilution mass spectrometry-equivalent SCr, were used for the validation. Bias, precision and accuracy (P30) were evaluated. RESULTS: The FAS equation was less biased [-1.7 (95% CI -3.4, -0.2) versus 6.0 (4.5, 7.5)] and more accurate [87.5% (85.1, 89.9) versus 83.8% (81.1, 86.5)] than the Schwartz equation for children and adolescents; less biased [5.0 (4.5, 5.5) versus 6.3 (5.9, 6.8)] and as accurate [81.6% (80.4, 82.7) versus 81.9% (80.7, 83.0)] as the CKD-EPI equation for young and middle-age adults; and less biased [-1.1 (-1.6, -0.6) versus 5.6 (5.1, 6.2)] and more accurate [86.1% (84.4, 87.7) versus 81.8% (79.7, 84.0)] than CKD-EPI for older adults. CONCLUSIONS: The FAS equation has improved validity and continuity across the full age-spectrum and overcomes the problem of implausible eGFR changes in patients which would otherwise occur when switching between more age-specific equations.

BACKGROUND: Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. METHODS: We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. CONCLUSIONS: Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. CLINICALTRIALS.GOV NUMBER: NCT00760838.

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127-0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363 .

BACKGROUND: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-β signaling. OBJECTIVES: This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS: We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS: Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-β signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-β signaling in association with up-regulation of the expression of TGF-β ligands. CONCLUSIONS: Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk.

Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely understood. Although the occluding thrombus is the primary target of acute treatment, little is known about its internal organization and composition. The aim of this study, therefore, was to better understand the internal organization of ischemic stroke thrombi on a molecular and cellular level. A total of 188 thrombi were collected from endovascularly treated ischemic stroke patients and analyzed histologically for fibrin, red blood cells (RBC), von Willebrand factor (vWF), platelets, leukocytes and DNA, using bright field and fluorescence microscopy. Our results show that stroke thrombi are composed of two main types of areas: RBC-rich areas and platelet-rich areas. RBC-rich areas have limited complexity as they consist of RBC that are entangled in a meshwork of thin fibrin. In contrast, platelet-rich areas are characterized by dense fibrin structures aligned with vWF and abundant amounts of leukocytes and DNA that accumulate around and in these platelet-rich areas. These findings are important to better understand why platelet-rich thrombi are resistant to thrombolysis and difficult to retrieve via thrombectomy, and can guide further improvements of acute ischemic stroke therapy.

AIMS: Chronic heart failure (CHF) patients are frequently rehospitalized within 6 months after an episode of fluid retention. Rehospitalizations are preventable, but this requires an extensive organization of the healthcare system. In this study, we tested whether intensive follow-up of patients through a telemonitoring-facilitated collaboration between general practitioners (GPs) and a heart failure clinic could reduce mortality and rehospitalization rate. METHODS AND RESULTS: One hunderd and sixty CHF patients [mean age 76 ± 10 years, 104 males, mean left ventricular ejection fraction (LVEF) 35 ± 15%] were block randomized by sealed envelopes and assigned to 6 months of intense follow-up facilitated by telemonitoring (TM) or usual care (UC). The TM group measured body weight, blood pressure, and heart rate on a daily basis with electronic devices that transferred the data automatically to an online database. Email alerts were sent to the GP and heart failure clinic to intervene when pre-defined limits were exceeded. All-cause mortality was significantly lower in the TM group as compared with the UC group (5% vs. 17.5%, P = 0.01). The total number of follow-up days lost to hospitalization, dialysis, or death was significantly lower in the TM group as compared with the UC group (13 vs. 30 days, P = 0.02). The number of hospitalizations for heart failure per patient showed a trend (0.24 vs. 0.42 hospitalizations/patient, P = 0.06) in favour of TM. CONCLUSION: Telemonitoring-facilitated collaboration between GPs and a heart failure clinic reduces mortality and number of days lost to hospitalization, death, or dialysis in CHF patients. These findings need confirmation in a large trial.

The overwhelming clinical benefit of intra-arterial stroke therapy owes to the major advance in revascularization brought on by the current generation of thrombectomy devices. Nevertheless, there remains a sizeable proportion of patients for whom substantial reperfusion cannot be achieved or is achieved too late. This article addresses the persistent challenges that face neurointerventionists and reviews technical refinements that may help to mitigate these obstacles to procedural success. Insights from in vitro modeling and clinical research are organized around a conceptual framework that examines the interaction between the device, the thrombus and the vessel wall.

BACKGROUND AND OBJECTIVES: The role of a fascia iliaca compartment block (FICB) for postoperative analgesia after total hip arthroplasty (THA) remains questionable. High-dose local anesthetics and a proximal injection site may be essential for successful analgesia. High-dose local anesthetics may pose a risk for local anesthetic systemic toxicity. We hypothesized that a high-dose longitudinal supra-inguinal FICB is safe and decreases postoperative morphine consumption after anterior approach THA. METHODS: We conducted a prospective, double blind, randomized controlled trial. Patients scheduled for THA were randomized to group FICB (longitudinal supra-inguinal FICB with 40-mL ropivacaine 0.5%) or group C (control, no block). Standard hypothesis tests (t test or Mann-Whitney U test, χ test) were performed to analyze baseline characteristics and outcome parameters. The primary end point of the study was total morphine (mg) consumption at 24 hours postoperatively. Serial total and free ropivacaine serum levels were determined in 10 patients. RESULTS: After obtaining ethical committee approval and written informed consent, 88 patients were included. Mean (SD) morphine consumption at 24 hours postoperatively was reduced in group FICB compared to group C: 10.25 (1.64) mg versus 19.0 (2.4) mg (P = 0.004). Using a mean dose of 2.6-mg/kg ropivacaine (range, 2-3.4 mg/kg), none of the patients had total or free ropivacaine levels above the maximum tolerated serum concentration. CONCLUSIONS: We conclude that a high-dose longitudinal supra-inguinal FICB reduces postoperative morphine requirements after anterior approach THA.Clinical Trials Registry: EU Clinical Trials Register. www.clinicaltrialsregister.eu #2014-002122-12.

BACKGROUND: The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear. METHODS: We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days. RESULTS: Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days. CONCLUSIONS: In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).

BACKGROUND: Previous studies have demonstrated that patient, surgical, tumour and operative variables affect the complexity of laparoscopic liver resections. However, current difficulty scoring systems address only tumour factors. The aim of this study was to develop and validate a predictive model for the risk of intraoperative complications during laparoscopic liver resections. METHODS: The prospectively maintained databases of seven European tertiary referral liver centres were compiled. Data from two-thirds of the patients were used for development and one-third for validation of the model. Intraoperative complications were based on a modified Satava classification. Using the methodology of the Framingham Heart Study, developed to identify risk factors that contribute to the development of cardiovascular disease, factors found to predict intraoperative complications independently were assigned points, and grouped into low-, moderate-, high- and extremely high-risk groups based on the likelihood of intraoperative complications. RESULTS: A total of 2856 patients were included. Neoadjuvant chemotherapy, lesion type and size, classification of resection and previous open liver resection were found to be independent predictors of intraoperative complications. Patients with intraoperative complications had a longer duration of hospital stay (5 versus 4 days; P < 0·001), higher complication rates (32·5 versus 15·5 per cent; P < 0·001), and higher 30-day (3·0 versus 0·3 per cent; P < 0·001) and 90-day (3·8 versus 0·8 per cent; P < 0·001) mortality rates than those who did not. The model was able to predict intraoperative complications (area under the receiver operating characteristic (ROC) curve (AUC) 0·677, 95 per cent c.i. 0·647 to 0·706) as well as postoperative 90-day mortality (AUC 0·769, 0·681 to 0·858). CONCLUSION: This comprehensive scoring system, based on patient, surgical and tumour factors, and developed and validated using a large multicentre European database, helped estimate the risk of intraoperative complications.

OBJECTIVE: The aim of the study was to validate and optimize the alternative Fistula Risk Score (a-FRS) for patients undergoing minimally invasive pancreatoduodenectomy (MIPD) in a large pan-European cohort. BACKGROUND: MIPD may be associated with an increased risk of postoperative pancreatic fistula (POPF). The a-FRS could allow for risk-adjusted comparisons in research and improve preventive strategies for high-risk patients. The a-FRS, however, has not yet been validated specifically for laparoscopic, robot-assisted, and hybrid MIPD. METHODS: A validation study was performed in a pan-European cohort of 952 consecutive patients undergoing MIPD (543 laparoscopic, 258 robot-assisted, 151 hybrid) in 26 centers from 7 countries between 2007 and 2017. The primary outcome was POPF (International Study Group on Pancreatic Surgery grade B/C). Model performance was assessed using the area under the receiver operating curve (AUC; discrimination) and calibration plots. Validation included univariable screening for clinical variables that could improve performance. RESULTS: Overall, 202 of 952 patients (21%) developed POPF after MIPD. Before adjustment, the original a-FRS performed moderately (AUC 0.68) and calibration was inadequate with systematic underestimation of the POPF risk. Single-row pancreatojejunostomy (odds ratio 4.6, 95 confidence interval [CI] 2.8-7.6) and male sex (odds ratio 1.9, 95 CI 1.4-2.7) were identified as important risk factors for POPF in MIPD. The updated a-FRS, consisting of body mass index, pancreatic texture, duct size, and male sex, showed good discrimination (AUC 0.75, 95 CI 0.71-0.79) and adequate calibration. Performance was adequate for laparoscopic, robot-assisted, and hybrid MIPD and open pancreatoduodenectomy. CONCLUSIONS: The updated a-FRS (www.pancreascalculator.com) now includes male sex as a risk factor and is validated for both MIPD and open pancreatoduodenectomy. The increased risk of POPF in laparoscopic MIPD was associated with single-row pancreatojejunostomy, which should therefore be discouraged.

The expression of certain bacterial genes is regulated in a cell-density dependent way, a phenomenon called quorum sensing. Both Gram-negative and Gram-positive bacteria use this type of communication, though the signal molecules (auto-inducers) used by them differ between both groups: Gram-negative bacteria use predominantly N-acyl homoserine lacton (AHL) molecules (autoinducer-1, AI-1) while Gram-positive bacteria use mainly peptides (autoinducer peptides, AIP or quorum sensing peptides). These quorum sensing molecules are not only involved in the inter-microbial communication, but can also possibly cross-talk directly or indirectly with their host. This review summarizes the currently applied analytical approaches for quorum sensing identification and quantification with additionally summarizing the experimentally found in vivo concentrations of these molecules in humans.

Rapid vascular recanalization forms the basis for successful treatment of cerebral ischemia. Currently, tissue plasminogen activator (t-PA) is the only approved thrombolytic drug for ischemic stroke. However, t-PA does not always result in efficient thrombus dissolution and subsequent blood vessel recanalization. To better understand thrombus composition, we analyzed thrombi retrieved from ischemic stroke patients and found a distinct presence of von Willebrand factor (VWF) in various samples. Thrombi contained on average 20.3% ± 10.1% VWF, and this was inversely correlated with thrombus red blood cell content. We hypothesized that ADAMTS13 can exert a thrombolytic effect in VWF-containing thrombi in the setting of stroke. To test this, we generated occlusive VWF-rich thrombi in the middle cerebral artery (MCA) of mice. Infusion of t-PA did not dissolve these MCA occlusions. Interestingly, administration of ADAMTS13 5 minutes after occlusion dose-dependently dissolved these t-PA-resistant thrombi resulting in fast restoration of MCA patency and consequently reduced cerebral infarct sizes (P < .005). Delayed ADAMTS13 administration 60 minutes after occlusion was still effective but to a lesser extent (P < .05). These data show for the first time a potent thrombolytic activity of ADAMTS13 in the setting of stroke, which might become useful in treatment of acute ischemic stroke.

PURPOSE: The purpose of this study is to propose recommendations for the treatment of patients with chronic lateral ankle instability (CAI) based on expert opinions. METHODS: A questionnaire was sent to 32 orthopaedic surgeons with clinical and scientific experience in the treatment of CAI. The questions were related to preoperative imaging, indications and timing of surgery, technical choices, and the influence of patient-related aspects. RESULTS: Thirty of the 32 invited surgeons (94%) responded. Consensus was found on several aspects of treatment. Preoperative MRI was routinely recommended. Surgery was considered in patients with functional ankle instability after 3-6 months of non-surgical treatment. Ligament repair is still the treatment of choice in patients with mechanical instability; however, in patients with generalized laxity or poor ligament quality, lateral ligament reconstruction (with grafting) of both the ATFL and CFL should be considered. CONCLUSIONS: Most surgeons request an MRI during the preoperative planning. There is a trend towards earlier surgical treatment (after failure of non-surgical treatment) in patients with mechanical ligament laxity (compared with functional instability) and in high-level athletes. This study proposes an assessment and a treatment algorithm that may be used as a recommendation in the treatment of patients with CAI. LEVEL OF EVIDENCE: V.

BACKGROUND: A new estimated glomerular filtration rate (eGFR) equation, designed for isotope dilution mass spectrometry-standardized serum creatinine (Scr), is presented for use in children, adolescent boys and girls and young adults. METHODS: The new equation, eGFR = 107.3/(Scr/Q), is based on the concept of normalized Scr: Q is the normalization value and is considered as the Scr concentration for the average healthy child, adolescent or young adult of a specific height (L) and is modeled as a height-dependent polynomial of the fourth degree. RESULTS: The well-known Schwartz equation [eGFR = kL/Scr, k = 0.413 (Schwartz) or k = 0.373 (Schwartz-Lyon)] for children between 1 and 14 years can be seen as a special case of the new equation for which the Q-polynomial is simplified to a linear equation: Q = 0.0035 × L (cm). The new eGFR equation has been validated in a data set of n = 750 children, adolescents and young adults aged 10-25, against the true GFR (inulin method), and outperforms the selected (but most used) creatinine-based eGFR equations for children, mainly in the healthy GFR region. CONCLUSIONS: The new Q(height)-eGFR equation serves as an excellent screening tool for kidney disease in 1-25-year-old children, adolescents and young adults.