Changes over time in epigenetic marks, which are modifications of DNA such as by DNA methylation, may help explain the late onset of common human diseases. However, changes in methylation or other ...epigenetic marks over time in a given individual have not yet been investigated.
To determine whether there are longitudinal changes in global DNA methylation in individuals and to evaluate whether methylation maintenance demonstrates familial clustering.
We measured global DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA sampled at 2 visits on average 11 years apart in 111 individuals from an Icelandic cohort (1991 and 2002-2005) and on average 16 years apart in 126 individuals from a Utah sample (1982-1985 and 1997-2005).
Global methylation changes over time.
Twenty-nine percent of Icelandic individuals showed greater than 10% methylation change over time (P < .001). The family-based Utah sample also showed intra-individual changes over time, and further demonstrated familial clustering of methylation change (P = .003). The family showing the greatest global methylation loss also demonstrated the greatest loss of gene-specific methylation by a separate methylation assay.
These data indicate that methylation changes over time and suggest that methylation maintenance may be under genetic control.
Abstract
Background
Studies have suggested that laparoscopic distal pancreatectomy (LDP) is advantageous compared with open distal pancreatectomy (ODP) regarding hospital stay, blood loss and ...recovery. Only one randomized study is available, which showed enhanced functional recovery after LDP compared with
ODP.
Methods
Consecutive patients evaluated at a multidisciplinary tumour board and planned for standard distal pancreatectomy were randomized prospectively to LDP or ODP in an unblinded, parallel-group, single-centre superiority trial. The primary outcome was postoperative hospital stay.
Results
Of 105 screened patients, 60 were randomized and 58 (24 women, 41 per cent) were included in the intention-to-treat analysis; there were 29 patients of mean age 68 years in the LDP group and 29 of mean age 63 years in the ODP group. The main indication was cystic pancreatic lesions, followed by neuroendocrine tumours. The median postoperative hospital stay was 5 (i.q.r. 4–5) days in the laparoscopic group versus 6 (5–7) days in the open group (P = 0·002). Functional recovery was attained after a median of 4 (i.q.r. 2–6) versus 6 (4–7) days respectively (P = 0·007), and duration of surgery was 120 min in both groups (P = 0·482). Blood loss was less with laparoscopic surgery: median 50 (i.q.r. 25–150) ml versus 100 (100–300) ml in the open group (P = 0·018). No difference was found in the complication rates (Clavien–Dindo grade III or above: 4 versus 8 patients respectively). The rate of delayed gastric emptying and clinically relevant postoperative pancreatic fistula did not differ between the groups.
Conclusion
LDP is associated with shorter hospital stay than ODP, with shorter time to functional recovery and less bleeding. Registration number: ISRCTN26912858 (www.isrctn.com).
Graphical Abstract
Laparoscopic distal pancreatectomy (LDP) was compared with open distal pancreatectomy (ODP) in a randomized trial. LDP was associated with shorter hospital stay, enhanced functional recovery, and less bleeding than ODP.
Graphical Abstract
Shorter hospital stay with laparoscopy
Postoperative pancreatic fistula is the leading cause of morbidity after distal pancreatectomy. Strategies investigated to reduce the incidence have been disappointing. Recent data showed a reduction ...in postoperative pancreatic fistula with the use of synthetic mesh reinforcement of the staple line.
An RCT was conducted between May 2014 and February 2016 at four tertiary referral centres in Sweden. Patients scheduled for distal pancreatectomy were eligible. Enrolled patients were randomized during surgery to stapler transection with biological reinforcement or standard stapler transection. Patients were blinded to the allocation. The primary endpoint was the development of any postoperative pancreatic fistula. Secondary endpoints included morbidity, mortality, and duration of hospital stay.
Some 107 patients were randomized and 106 included in an intention-to-treat analysis (56 in reinforced stapling group, 50 in standard stapling group). No difference was demonstrated in terms of clinically relevant fistulas (grade B and C): 6 of 56 (11 per cent) with reinforced stapling versus 8 of 50 (16 per cent) with standard stapling (P = 0.332). There was no difference between groups in overall postoperative complications: 45 (80 per cent) and 39 (78 per cent) in reinforced and standard stapling groups respectively (P = 0.765). Duration of hospital stay was comparable: median 8 (range 2-35) and 9 (2-114) days respectively (P = 0.541).
Biodegradable stapler reinforcement at the transection line of the pancreas did not reduce postoperative pancreatic fistula compared with regular stapler transection in distal pancreatectomy. Registration number: NCT02149446 (http://www.clinicaltrials.gov).
Crust at many divergent plate boundaries forms primarily by the injection of vertical sheet-like dykes, some tens of kilometres long. Previous models of rifting events indicate either lateral dyke ...growth away from a feeding source, with propagation rates decreasing as the dyke lengthens, or magma flowing vertically into dykes from an underlying source, with the role of topography on the evolution of lateral dykes not clear. Here we show how a recent segmented dyke intrusion in the Bárðarbunga volcanic system grew laterally for more than 45 kilometres at a variable rate, with topography influencing the direction of propagation. Barriers at the ends of each segment were overcome by the build-up of pressure in the dyke end; then a new segment formed and dyke lengthening temporarily peaked. The dyke evolution, which occurred primarily over 14 days, was revealed by propagating seismicity, ground deformation mapped by Global Positioning System (GPS), interferometric analysis of satellite radar images (InSAR), and graben formation. The strike of the dyke segments varies from an initially radial direction away from the Bárðarbunga caldera, towards alignment with that expected from regional stress at the distal end. A model minimizing the combined strain and gravitational potential energy explains the propagation path. Dyke opening and seismicity focused at the most distal segment at any given time, and were simultaneous with magma source deflation and slow collapse at the Bárðarbunga caldera, accompanied by a series of magnitude M > 5 earthquakes. Dyke growth was slowed down by an effusive fissure eruption near the end of the dyke. Lateral dyke growth with segment barrier breaking by pressure build-up in the dyke distal end explains how focused upwelling of magma under central volcanoes is effectively redistributed over long distances to create new upper crust at divergent plate boundaries.
Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and ...replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94-0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65-0.78), but further technical and clinical validation of these candidate biomarkers is needed.
Digital twins to personalize medicine Björnsson, Bergthor; Borrebaeck, Carl; Elander, Nils ...
Genome medicine,
12/2019, Letnik:
12, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are ...high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.
Periprosthetic joint infection is a serious complication and a major reason for revision surgery after primary shoulder arthroplasty. The prophylactic antibiotics for primary shoulder arthroplasty ...that have predominantly been used in Sweden are cloxacillin and clindamycin. To address Cutibacteriumacnes , benzylpenicillin has recently increasingly been added to cloxacillin, but it is unclear which antibiotic prophylaxis regimen is the most effective to prevent periprosthetic joint infection.
After controlling for baseline differences among patients such as age, gender, previous surgery, cement fixation, and arthroplasty type, was the risk of reoperation for infection higher in patients who received cloxacillin than in those who received clindamycin or the combination of benzylpenicillin and cloxacillin?
Data from the Swedish Shoulder Arthroplasty Register were used for this study. The inclusion criterion was registered antibiotic prophylaxis in primary arthroplasty. Between January 1, 1999, and December 31, 2019, 22,470 primary shoulder arthroplasties, including total shoulder, hemiarthroplasty, and reverse shoulder arthroplasties, were entered into the Swedish Shoulder Arthroplasty Register. Reporting of antibiotic prophylaxis to the register was introduced on January 1, 2013. Since then, the completeness of information on the type of antibiotic prophylaxis in the reports has been 85.3%. Consequently, 10,706 arthroplasties were eligible and fulfilled the inclusion criterion of reported antibiotic prophylaxis. A further 129 were excluded because of unusual prophylaxis regimens, leaving 10,577 shoulder arthroplasties for analysis. The Swedish Shoulder Arthroplasty Register gathers information from all 60 hospitals performing shoulder arthroplasty in Sweden, and through a comparison with the National Patient Register, it has been estimated that more than 90% of all primary shoulder arthroplasties and shoulder reoperations are reported to the register. The age of the study population ranged between 16 and 98 years; the mean age at the primary surgery was 70 ± 10 years for the entire cohort, with a mean age of 67 ± 10 years and 72 ± 9 years for men and women, respectively. The mean observation period was 989 ± 669 days. From 2013 to 2019, there was a clear change in prophylaxis; in particular, the use of the combination of benzylpenicillin and cloxacillin increased dramatically and the use of cloxacillin alone decreased. Clindamycin prophylaxis increased moderately. The primary study endpoint was reported reoperation for infection. In the register, this is defined as repeat procedures of any kind, including biopsy, lavage of the joint, or revision, defined as secondary surgery in which a component was exchanged, removed, or added. To compare the reoperation rate in relation to the different antibiotics used, which changed over time, we controlled for age, gender, previous surgery, cement fixation, and arthroplasty type using a Cox proportional hazards model.
When adjusting for age, gender, previous surgery, cement fixation, and arthroplasty type, cloxacillin prophylaxis was associated with an increased relative risk of reoperation for infection compared with the combination of cloxacillin and benzylpenicillin (hazard ratio HR 2.40 95% confidence interval (CI) 1.35 to 4.25; p = 0.003) and compared with clindamycin alone (HR 1.78 95% CI 1.11 to 2.85; p = 0.02). No difference was found between the cloxacillin and benzylpenicillin combination and clindamycin (HR 0.74 95% CI 0.42 to 1.32; p = 0.31).
Our results indicate that prophylaxis against C. acnes may be warranted in shoulder arthroplasty. Because the absolute number of infections was low and infections could have been underreported to the register, our results should be interpreted with caution. There is no available information about the causative microorganisms. The study lays the groundwork for further investigations of antibiotic prophylaxis regimens in shoulder arthroplasty. Because large randomized controlled trials would be impractical to perform, prospective register-based randomized controlled studies might be a viable method.
Level Ⅲ, therapeutic study.
Some patients prescribed flucloxacillin (~ 0.01%) develop drug‐induced liver injury (DILI). HLA‐B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, ...identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single‐nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA‐B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10−97). HLA‐B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10−6). Within the HLA‐B protein sequence, imputation showed valine97, common to HLA‐B*57:01 and HLA‐B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10−97). We found no HLA‐B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non‐HLA signals for any penicillin‐related DILI.
Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 ...Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10
) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10
). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10
) and aortic root diameter (P = 1.30 × 10
), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10
) and coronary artery disease (OR = 1.05, P = 9.3 × 10
). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.
PDF
