Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Outcome of Pancreatic Surgery During the First Six Years of a Mandatory Audit within the Dutch Pancreatic Cancer Group

OBJECTIVE: To describe outcome after pancreatic surgery in the first six years of a mandatory nationwide audit.BACKGROUND: Within the Dutch Pancreatic Cancer Group, efforts have been made to improve outcome after pancreatic surgery. These include collaborative projects, clinical auditing, and implementation of an algorithm for early recognition and management of postoperative complications. However, nationwide changes in outcome over time have not yet been described.METHODS: This nationwide cohort study included consecutive patients after pancreatoduodenectomy and distal pancreatectomy from the mandatory Dutch Pancreatic Cancer Audit (January 2014-December 2019). Patient, tumor, and treatment characteristics were compared between three time periods (2014-2015, 2016-2017, and 2018-2019). Short-term surgical outcome was investigated using multilevel multivariable logistic regression analyses. Primary endpoints were failure to rescue and in-hospital mortality.RESULTS: Overall, 5345 patients were included, of whom 4227 after pancreatoduodenectomy and 1118 after distal pancreatectomy. After pancreatoduodenectomy, failure to rescue improved from 13% to 7.4% (OR 0.64, 95%CI 0.50-0.80, P&lt;0.001) and in-hospital mortality decreased from 4.1% to 2.4% (OR 0.68, 95%CI 0.54-0.86, P=0.001), despite operating on more patients with age &gt;75 years (18% to 22%, P=0.006), ASA score ≥3 (19% to 31%, P&lt;0.001) and Charlson comorbidity score ≥2 (24% to 34%, P&lt;0.001). The rates of textbook outcome (57% to 55%, P=0.283) and major complications remained stable (31% to 33%, P=0.207), whereas complication-related intensive care admission decreased (13% to 9%, P=0.002). After distal pancreatectomy, improvements in failure to rescue from 8.8% to 5.9% (OR 0.65, 95%CI 0.30-1.37, P=0.253) and in-hospital mortality from 1.6% to 1.3% (OR 0.88, 95%CI 0.45-1.72, P=0.711) were not statistically significant.CONCLUSIONS: During the first six years of a nationwide audit, in-hospital mortality and failure to rescue after pancreatoduodenectomy improved despite operating on more high-risk patients. Several collaborative efforts may have contributed to these improvements.</p

Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 μg) and folic acid (400 μg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT0069651

Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial

Introduction: Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old, and is associated with elevated arterial stiffness in this age group. Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes, we aimed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients. Methods: The B-PROOF study is a double-blind, randomized controlled trial, including 2919 elderly aged at least 65 years, with hyperhomocysteinemia (12-50mol/l), treated with B-vitamins (500g vitamin B12 and 400g folic acid) or placebo for 2 years. In a subgroup (n=569), the effect of B-vitamins on pulse wave velocity (PWV) was investigated as a measurement of arterial stiffness. To measure atherosclerosis, carotid intima-media thickness (IMT) measures had been used. Incidents of cardiovascular and cerebrovascular events were determined via structured questionnaires, and blood pressure was also measured. Results: Compared to placebo, B-vitamin supplementation lowered serum homocysteine by 3.6mol/l (P <0.001). Analysis of covariance showed no effect of supplementation on PWV levels, and this was not different for patients without increased arterial stiffness at baseline. Furthermore, no effect on carotid IMT was observed. Discussion: Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT. Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcome

Outcome of Pancreatic Surgery During the First Six Years of a Mandatory Audit within the Dutch Pancreatic Cancer Group

OBJECTIVE: To describe outcome after pancreatic surgery in the first six years of a mandatory nationwide audit. BACKGROUND: Within the Dutch Pancreatic Cancer Group, efforts have been made to improve outcome after pancreatic surgery. These include collaborative projects, clinical auditing, and implementation of an algorithm for early recognition and management of postoperative complications. However, nationwide changes in outcome over time have not yet been described. METHODS: This nationwide cohort study included consecutive patients after pancreatoduodenectomy and distal pancreatectomy from the mandatory Dutch Pancreatic Cancer Audit (January 2014-December 2019). Patient, tumor, and treatment characteristics were compared between three time periods (2014-2015, 2016-2017, and 2018-2019). Short-term surgical outcome was investigated using multilevel multivariable logistic regression analyses. Primary endpoints were failure to rescue and in-hospital mortality. RESULTS: Overall, 5345 patients were included, of whom 4227 after pancreatoduodenectomy and 1118 after distal pancreatectomy. After pancreatoduodenectomy, failure to rescue improved from 13% to 7.4% (OR 0.64, 95%CI 0.50-0.80, P75 years (18% to 22%, P=0.006), ASA score ≥3 (19% to 31%, P<0.001) and Charlson comorbidity score ≥2 (24% to 34%, P<0.001). The rates of textbook outcome (57% to 55%, P=0.283) and major complications remained stable (31% to 33%, P=0.207), whereas complication-related intensive care admission decreased (13% to 9%, P=0.002). After distal pancreatectomy, improvements in failure to rescue from 8.8% to 5.9% (OR 0.65, 95%CI 0.30-1.37, P=0.253) and in-hospital mortality from 1.6% to 1.3% (OR 0.88, 95%CI 0.45-1.72, P=0.711) were not statistically significant. CONCLUSIONS: During the first six years of a nationwide audit, in-hospital mortality and failure to rescue after pancreatoduodenectomy improved despite operating on more high-risk patients. Several collaborative efforts may have contributed to these improvements

Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours (LEOPARD-2): a multicentre, patient-blinded, randomised controlled phase 2/3 trial

Background: Laparoscopic pancreatoduodenectomy may improve postoperative recovery compared with open pancreatoduodenectomy. However, there are concerns that the extensive learning curve of this complex procedure could increase the risk of complications. We aimed to assess whether laparoscopic pancreatoduodenectomy could reduce time to functional recovery compared with open pancreatoduodenectomy. Methods: This multicentre, patient-blinded, parallel-group, randomised controlled phase 2/3 trial was performed in four centres in the Netherlands that each do 20 or more pancreatoduodenectomies annually; surgeons had to have completed a dedicated training programme for laparoscopic pancreatoduodenectomy and have done 20 or more laparoscopic pancreatoduodenectomies before trial participation. Patients with a benign, premalignant, or malignant indication for pancreatoduodenectomy, without signs of vascular involvement, were randomly assigned (1:1) to undergo either laparoscopic or open pancreatoduodenectomy using a central web-based system. Randomisation was stratified for annual case volume and preoperative estimated risk of pancreatic fistula. Patients were blinded to treatment allocation. Analysis was done according to the intention-to-treat principle. The main objective of the phase 2 part of the trial was to assess the safety of laparoscopic pancreatoduodenectomy (complications and mortality), and the primary outcome of phase 3 was time to functional recovery in days, defined as all of the following: adequate pain control with only oral analgesia; independent mobility; ability to maintain more than 50% of the daily required caloric intake; no need for intravenous fluid administration; and no signs of infection (temperature <38·5°C). This trial is registered with Trialregister.nl, number NTR5689. Findings: Between May 13 and Dec 20, 2016, 42 patients were randomised in the phase 2 part of the trial. Two patients did not receive surgery and were excluded from analyses in accordance with the study protocol. Three (15%) of 20 patients died within 90 days after laparoscopic pancreatoduodenectomy, compared with none of 20 patients after open pancreatoduodenectomy. Based on safety data from the phase 2 part of the trial, the data and safety monitoring board and protocol committee agreed to proceed with phase 3. Between Jan 31 and Nov 14, 2017, 63 additional patients were randomised in phase 3 of the trial. Four patients did not receive surgery and were excluded from analyses in accordance with the study protocol. After randomisation of 105 patients (combining patients from both phase 2 and phase 3), of whom 99 underwent surgery, the trial was prematurely terminated by the data and safety monitoring board because of a difference in 90-day complication-related mortality (five [10%] of 50 patients in the laparoscopic pancreatoduodenectomy group vs one [2%] of 49 in the open pancreatoduodenectomy group; risk ratio [RR] 4·90 [95% CI 0·59–40·44]; p=0·20). Median time to functional recovery was 10 days (95% CI 5–15) after laparoscopic pancreatoduodenectomy versus 8 days (95% CI 7–9) after open pancreatoduodenectomy (log-rank p=0·80). Clavien-Dindo grade III or higher complications (25 [50%] of 50 patients after laparoscopic pancreatoduodenectomy vs 19 [39%] of 49 after open pancreatoduodenectomy; RR 1·29 [95% CI 0·82–2·02]; p=0·26) and grade B/C postoperative pancreatic fistulas (14 [28%] vs 12 [24%]; RR 1·14 [95% CI 0·59–2·22]; p=0·69) were comparable between groups. Interpretation: Although not statistically significant, laparoscopic pancreatoduodenectomy was associated with more complication-related deaths than was open pancreatoduodenectomy, and there was no difference between groups in time to functional recovery. These safety concerns were unexpected and worrisome, especially in the setting of trained surgeons working in centres performing 20 or more pancreatoduodenectomies annually. Experience, learning curve, and annual volume might have influenced the outcomes; future research should focus on these issues. Funding: Grant for investigator-initiated studies by Johnson & Johnson Medical Limited