The prognosis of kidney transplant recipients with aorto-iliac calcification: a systematic review and meta-analysis

The prognosis of kidney transplant recipients (KTR) with vascular calcification (VC) in the aorto-iliac arteries is unclear. We performed a systematic review and meta-analysis to investigate their survival outcomes. Studies from January 1st, 2000 until March 5th, 2019 were included. Outcomes for meta-analysis were patient survival, (death-censored) graft survival and delayed graft function (DGF). Twenty-one studies were identified, eight provided data for meta-analysis. KTR with VC had a significantly increased mortality risk [1-year: risk ratio (RR) 2.19 (1.39–3.44), 5-year: RR 2.28 (1.86–2.79)]. The risk of 1-year graft loss was three times higher in recipients with VC [RR 3.15 (1.30–7.64)]. The risk of graft loss censored for death [1-year: RR 2.26 (0.58–2.73), 3-year: RR 2.19 (0.49–9.82)] and the risk of DGF (RR 1.24, 95% CI 0.98–1.58) were not statistically different. The quality of the evidence was rated as very low. To conclude, the presence of VC was associated with an increased mortality risk and risk of graft loss. In this small sample size, no statistical significant association between VC and DGF or risk of death-censored graft loss could be demonstrated. For interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration

Direct Evidence of Endothelial Dysfunction and Glycocalyx Loss in Dermal Biopsies of Patients With Chronic Kidney Disease and Their Association With Markers of Volume Overload

Cardiovascular morbidity is a major problem in patients with chronic kidney disease (CKD) and endothelial dysfunction (ED) is involved in its development. The luminal side of the vascular endothelium is covered by a protective endothelial glycocalyx (eGC) and indirect evidence indicates eGC loss in CKD patients. We aimed to investigate potential eGC loss and ED in skin biopsies of CKD patients and their association with inflammation and volume overload. During living kidney transplantation procedure, abdominal skin biopsies were taken from 11 patients with chronic kidney disease stage 5 of whom 4 were treated with hemodialysis and 7 did not receive dialysis treatment. Nine healthy kidney donors served as controls. Biopsies were stained and quantified for the eGC marker Ulex europaeus agglutinin-1 (UEA1) and the endothelial markers vascular endothelial growth factor-2 (VEGFR2) and von Willebrand factor (vWF) after double staining and normalization for the pan-endothelial marker cluster of differentiation 31. We also studied associations between quantified log-transformed dermal endothelial markers and plasma markers of inflammation and hydration status. Compared to healthy subjects, there was severe loss of the eGC marker UEA1 (P < 0.01) while VEGFR2 was increased in CKD patients, especially in those on dialysis (P = 0.01). For vWF, results were comparable between CKD patients and controls. Skin water content was identical in the three groups, which excluded dermal edema as an underlying cause in patients with CKD. The dermal eGC/ED markers UEA1, VEGFR2, and vWF all associated with plasma levels of NT-proBNP and sodium (all R2 > 0.29 and P < 0.01), except for vWF that only associated with plasma NT-proBNP. This study is the first to show direct histopathological evidence of dermal glycocalyx loss and ED in patients with CKD. In line with previous research, our results show that ED associates with markers of volume overload arguing for strict volume control in CKD patients

Machine-perfused donor kidneys as a source of human renal endothelial cells

Renal endothelial cells (ECs) play crucial roles in vasorelaxation, ultrafiltration, and selective transport of electrolytes and water, but also in leakage of the glomerular filtration barrier and inflammatory processes like complement activation and leukocyte recruitment. In addition, they are target cells for both cellular and antibody-mediated rejection in the transplanted kidney. To study the molecular and cellular processes underlying EC behavior in renal disease, well-characterized primary renal ECs are indispensible. In this report, we describe a straightforward procedure to isolate ECs from the perfusion fluid of human donor kidneys by a combination of negative selection of monocytes/macrophages, positive selection by CD31 Dynabeads, and propagation in endothelium-specific culture medium. Thus, we isolated and propagated renal ECs from 102 donor kidneys, representative of all blood groups and major human leukocyte antigen (HLA) class I and II antigens. The obtained ECs were positive for CD31 and von Willebrand factor, expressed other endothelial markers such as CD34, VEGF receptor-2, TIE2, and plasmalemmal vesicle associated protein-1 to a variable extent, and were negative for the monocyte marker CD14 and lymphatic endothelial marker podoplanin. HLA class II was either constitutively expressed or could be induced by interferon-y. Furthermore, as a proof of principle, we showed the diagnostic value of this renal endothelial biobank in renal endothelium-specific cross-matching tests for HLA antibodies. NEW & NOTEWORTHY We describe a new and widely accessible approach to obtain human primary renal endothelial cells in a \standardized fashion, by isolating from the perfusate of machine-perfused donor kidneys. Characterization of the cells showed a mixed population originating from different compartments of the kidney. As a proof of principle, we demonstrated a possible diagnostic application in an endothelium-specific cross-match. Next to transplantation, we foresee further applications in the field renal endothelial research

Pancreatic resection in the pediatric, adolescent and young adult population:nationwide analysis on complications

Background: The aim of this study was to determine pancreatic surgery specific short- and long-term complications of pediatric, adolescent and young adult (PAYA) patients who underwent pancreatic resection, as compared to a comparator cohort of adults. Methods: A nationwide retrospective cohort study was performed in PAYA patients who underwent pancreatic resection between 2007 and 2016. PAYA was defined as all patients <40 years at time of surgery. Pancreatic surgery-specific complications were assessed according to international definitions and textbook outcome was determined. Results: A total of 230 patients were included in the PAYA cohort (112 distal pancreatectomies, 99 pancreatoduodenectomies), and 2526 patients in the comparator cohort. For pancreatoduodenectomy, severe morbidity (29.3% vs. 28.6%; P = 0.881), in-hospital mortality (1% vs. 4%; P = 0.179) and textbook outcome (62% vs. 58%; P = 0.572) were comparable between the PAYA and the comparator cohort. These outcomes were also similar for distal pancreatectomy. After pancreatoduodenectomy, new-onset diabetes mellitus (8% vs. 16%) and exocrine pancreatic insufficiency (27% vs. 73%) were lower in the PAYA cohort when compared to adult literature. Conclusion: Pancreatic surgery-specific complications were comparable with patients ≥40 years. Development of endocrine and exocrine insufficiency in PAYA patients who underwent pancreatoduodenectomy, however, was substantially lower compared to adult literature

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers.METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test.RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501).CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.</p

Screening for colorectal cancer after pancreatoduodenectomy for ampullary cancer

Background: In some Dutch pancreatic surgery centers, patients who underwent pancreatoduodenectomy (PD) for ampullary cancer undergo surveillance for colorectal cancer (CRC), since an association is suggested in contemporary literature. This study aimed to examine the CRC incidence after PD for ampullary cancer in four pancreatic surgery centers and a Dutch nationwide cohort. Methods: All patients who underwent resection of ampullary cancer from 2005 through 2017 at four centers were included. All colonoscopies and CRC diagnoses in these patients were recorded. In addition all PDs for ampullary cancer in the Dutch Pathology Registry (2000–2017) were recorded along with the CRC diagnoses and compared with an age, sex, and year-matched cohort. Results: Out of 287 included patients by the four centers, 11% underwent a colonoscopy within one year after PD. Eight (2.7%) were diagnosed with CRC before PD and two (0.7%), at 14 and 72 months after PD. In the nationwide cohort comparison, the CRC incidence was similar before (2.6% versus 1.9%, P = 0.424) and after surgery (2.1% versus 3.1%, P = 0.237). Within one year after PD, the incidence was 0.3% compared to 0.6% in the matched controls (P = 0.726). Conclusions: The current study could not find an increased risk of CRC in patients with resected ampullary cancer. Therefore, there is insufficient justification to screen for CRC in patients with resected ampullary cancer

Measurements of ψ(2S) and X(3872) → J/ψπ+π− production in pp collisions at √s=8 TeV with the ATLAS detector

Differential cross sections are presented for the prompt and non-prompt production of the hidden-charm states X(3872) and ψ(2S), in the decay mode J/ψπ+π−, measured using 11.4 fb−1 of pp collisions at √s=8 TeV by the ATLAS detector at the LHC. The ratio of cross-sections X(3872)/ψ(2S) is also given, separately for prompt and non-prompt components, as well as the non-prompt fractions of X(3872) and ψ(2S). Assuming independent single effective lifetimes for non-prompt X(3872) and ψ(2S) production gives RB=B(B→X(3872)+any)B(X(3872)→J/ψπ+π−)B(B→ψ(2S)+any)B(ψ(2S)→J/ψπ+π−)=(3.95±0.32(stat)±0.08(sys))×10−2RB=B(B→X(3872)+any)B(X(3872)→J/ψπ+π−)B(B→ψ(2S)+any)B(ψ(2S)→J/ψπ+π−)=(3.95±0.32(stat)±0.08(sys))×10−2 separating short- and long-lived contributions, assuming that the short-lived component is due to Bc decays, gives RB = (3.57 ± 0.33(stat) ± 0.11(sys)) × 10−2, with the fraction of non-prompt X(3872) produced via Bc decays for pT(X(3872)) > 10 GeV being (25 ± 13(stat) ± 2(sys) ± 5(spin))%. The distributions of the dipion invariant mass in the X(3872) and ψ(2S) decays are also measured and compared to theoretical predictions

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p