Large-scale Bayesian Structure Learning for Gaussian Graphical Models using Marginal Pseudo-likelihood

Bayesian methods for learning Gaussian graphical models offer a robust framework that addresses model uncertainty and incorporates prior knowledge. Despite their theoretical strengths, the applicability of Bayesian methods is often constrained by computational needs, especially in modern contexts involving thousands of variables. To overcome this issue, we introduce two novel Markov chain Monte Carlo (MCMC) search algorithms that have a significantly lower computational cost than leading Bayesian approaches. Our proposed MCMC-based search algorithms use the marginal pseudo-likelihood approach to bypass the complexities of computing intractable normalizing constants and iterative precision matrix sampling. These algorithms can deliver reliable results in mere minutes on standard computers, even for large-scale problems with one thousand variables. Furthermore, our proposed method is capable of addressing model uncertainty by efficiently exploring the full posterior graph space. Our simulation study indicates that the proposed algorithms, particularly for large-scale sparse graphs, outperform the leading Bayesian approaches in terms of computational efficiency and precision. The implementation supporting the new approach is available through the R package BDgraph.Comment: 34 page

Accuracy Of Whole Slide Imaging Stack Alignment In Consecutive Sections Of The Carotid Artery

Introduction/ Background Atherosclerosis is a chronic inflammatory disease of middle-sized and large arteries, characterized by the accumulation of inflammatory cells, especially mac- rophages [1] . A detailed visualization of the presence and distribution of macrophages in the atherosclerotic plaque contributes to a better understanding of the pathogenesis of atherosclerosis and the onset of acute coronary syndromes after atherosclerotic plaque rup- ture. Three-dimensional (3D) reconstruction of histology sections has the potential to improve both the detection of lesions as well as understanding in plaque growth and destabilization. Aims The objective of this study is to implement a image marker independent 3D histology reconstruction method in order to visualize the arteriosclerotic vessel and evaluate its accuracy. Methods A dataset comprising 48 consecutive cross-sections with a slice thickness of 10µm of a formalin-fixed paraf- fin-embedded (FFPE) carotid artery was used. The slideswere double stained with monoclonal antibodies and were scanned with anOlympusdotSlide scanner with a 10x objective leading to 0.65 micron pixel size. In these images, the smooth muscle cells and macrophages were visualized in blue and red, respectively. Rigid, rigid & affine, and rigid & affine & b-spline (non-rigid) automatic stack alignment was performed using elastix, an open-source toolbox for alignment of images [2]. As a consequence of the image deformation in non-rigid approaches, the diagnostic accuracy might be hindered. Therefore a small bending energy, i.e., sum of the spatial second-order derivatives of the transformation, was al- lowed. In order to increase processing speed, the stack alignment was performed on downsampled data.   An automatically determined mask of the vessel was used for pair-wise reconstruction of the vessel with re- spect to the middle slide that was chosen as a reference section. Accuracy was visually assessed using a surface plot of the lumen of the vessel. In addition, the Dice similarity coefficient, which is a measure of spatial image overlap, of consecutive pairs of slides was calculated for the different stack alignment approaches. Results Visual assessment of the surface plot of the vessels’ lu- men after pair-wise stack alignment, showed a relatively smooth surface of the lumen. This was the case for the rigid (i.e. translation and rotation), rigid & affine, and rigid & affine & b-spline approaches.  The Dice similarity coefficient of the registered masks increased with each additional alignment step. Slides alignment using rigid, rigid & affine and rigid & affine & b-spline approaches resulted in average Dice similarity coefficient of 0.85, 0.87, and 0.98, respectively. A more accurate result of the alignment comes at the cost of an increase in computation time by roughly a factor of two in each additional alignment step

Dutch Outcome in Implantable Cardioverter-Defibrillator Therapy:Implantable Cardioverter-Defibrillator-Related Complications in a Contemporary Primary Prevention Cohort

Background One third of primary prevention implantable cardioverter-defibrillator patients receive appropriate therapy, but all remain at risk of defibrillator complications. Information on these complications in contemporary cohorts is limited. This study assessed complications and their risk factors after defibrillator implantation in a Dutch nationwide prospective registry cohort and forecasts the potential reduction in complications under distinct scenarios of updated indication criteria. Methods and Results Complications in a prospective multicenter registry cohort of 1442 primary implantable cardioverter-defibrillator implant patients were classified as major or minor. The potential for reducing complications was derived from a newly developed prediction model of appropriate therapy to identify patients with a low probability of benefitting from the implantable cardioverter-defibrillator. During a follow-up of 2.2 years (interquartile range, 2.0-2.6 years), 228 complications occurred in 195 patients (13.6%), with 113 patients (7.8%) experiencing at least one major complication. Most common ones were lead related (n=93) and infection (n=18). Minor complications occurred in 6.8% of patients, with lead-related (n=47) and pocket-related (n=40) complications as the most prevailing ones. A surgical reintervention or additional hospitalization was required in 53% or 61% of complications, respectively. Complications were strongly associated with device type. Application of stricter implant indication results in a comparable proportional reduction of (major) complications. Conclusions One in 13 patients experiences at least one major implantable cardioverter-defibrillator-related complication, and many patients undergo a surgical reintervention. Complications are related to defibrillator implantations, and these should be discussed with the patient. Stricter implant indication criteria and careful selection of device type implanted may have significant clinical and financial benefits

Screening for type 2 diabetes and hypertension in seafarers' medical examinations

BACKGROUND: The aims of the study are: 1) to replace the urine glucose test for diabetes with more than 50% false negatives, with an accurate screening for type 2 diabetes and hypertension in the mandatory biannual fit-for-duty medical examinations of seafarers; 2) to produce data driven "Green Ship" health pro-motion in the ships. A new health promotion and disease prevention public health intervention programme integrated in the fit-for-duty medical examinations for seafarers is being developed. MATERIALS AND METHODS: The lack of an accurate diagnosis of type 2 diabetes is replaced by accurate HbA1c and/or fasting glucose tests and the test for hypertension in various disease stages is based on the International Associations' Guidelines. A "Green Ship" health promotion programme is proposed for all on board, not only for diseased crew members. RESULTS: A protocol for an accurate biannual screening for diabetes and hypertension is presented. Educational programmes for medical doctors and seafarers on the management of hypertension and diabetes on board will be developed. Presuming that all crew members are potentially on their way to be pre-diseased or are diseased, the "Green Ship" health promotion programme is implemented for the whole crew. CONCLUSIONS: The International Labour Organization and the National Maritime Authorities are prompted to revise the International and the National Guidelines for Seafarers Medical Examinations, respectively. Con-certed actions are requested to implement public health promotion projects in shipping. Maritime medical doctors are prompted to use health dialogues and to report the clinical data in the Excel file. Sustainability is obtained by complying with the Sustainable Development Goals (3, 4, 8, 10, and 17)

DNA methylation and body mass index from birth to adolescence : meta-analyses of epigenome-wide association studies

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P <1.06 x 10(-7), with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P-enrichment = 1; childhood P-enrichment = 2.00 x 10(-4); adolescence P-enrichment = 2.10 x 10(-7)). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.Peer reviewe

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 x 10(-7), with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P-enrichment = 1; childhood P-enrichment = 2.00 x 10(-4); adolescence P-enrichment = 2.10 x 10(-7)). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The transient impact of the African monsoon on Plio-Pleistocene Mediterranean sediments

Over the Plio-Pleistocene interval a strong linkage exists between northern African climate changes and the supply of dust over the surrounding oceans and continental runoff towards the Mediterranean Sea. Both these signatures in the sedimentary record are determined by orbital cycles influencing glacial variability on the one hand and northern African monsoon intensity on the other hand. In this paper, we use the intermediate-complexity model CLIMBER- 2 to simulate African climate during the Plio-Pleistocene between 3.2 and 2.3 million years ago (Ma) and compare our simulations with existing and new climate reconstructions. The CLIMBER-2 model is externally forced with atmospheric CO2 concentrations, ice sheet topography, and orbital variations, all of which strongly influence climate during the Pliocene and Pleistocene. Our simulations indicate that the records of northern Africa climate oscillate in phase with climatic precession. For the Earth's obliquity cycle, the time lag between the 41 000-year component in insolation forcing and the climatic response increased after inception of Northern Hemisphere (NH) glaciation around 2.8 Ma. To test the outcome of our simulations, we have put emphasis on the comparison between the simulated runoff of grid boxes encompassing the Sahara desert and the Sahel region and the sedimentary records of marine sediment cores from ODP Site 659 (Atlantic Ocean) and ODP Site 967 (Mediterranean). In this study we will show for the first time an extended Ti=Al record of Site 967 down to 3.2 Ma. This record strongly correlates with runoff in the Sahara and Sahel regions, whereas correlation with the dust record of Site 659 is moderate and slightly improves after NH ice sheet inception. We investigated the transient variability of the individual and combined contributions of the Sahel and Sahara regions and found significant transient behaviour overlapping the inception of NH ice sheets (2.8 Ma) and the Plio-Pleistocene transition (2.6 Ma). Prior to 2.8 Ma, a larger contribution from the Sahara region is required to explain the variability of Mediterranean dust input. After this transition, we found that a more equal contribution of the two regions is required, representing an increased influence of Sahel runoff and wet periods

The transient impact of the African monsoon on Plio-Pleistocene Mediterranean sediments

Over the Plio-Pleistocene interval a strong linkage exists between northern African climate changes and the supply of dust over the surrounding oceans and continental runoff towards the Mediterranean Sea. Both these signatures in the sedimentary record are determined by orbital cycles influencing glacial variability on the one hand and northern African monsoon intensity on the other hand. In this paper, we use the intermediate-complexity model CLIMBER- 2 to simulate African climate during the Plio-Pleistocene between 3.2 and 2.3 million years ago (Ma) and compare our simulations with existing and new climate reconstructions. The CLIMBER-2 model is externally forced with atmospheric CO2 concentrations, ice sheet topography, and orbital variations, all of which strongly influence climate during the Pliocene and Pleistocene. Our simulations indicate that the records of northern Africa climate oscillate in phase with climatic precession. For the Earth's obliquity cycle, the time lag between the 41 000-year component in insolation forcing and the climatic response increased after inception of Northern Hemisphere (NH) glaciation around 2.8 Ma. To test the outcome of our simulations, we have put emphasis on the comparison between the simulated runoff of grid boxes encompassing the Sahara desert and the Sahel region and the sedimentary records of marine sediment cores from ODP Site 659 (Atlantic Ocean) and ODP Site 967 (Mediterranean). In this study we will show for the first time an extended Ti=Al record of Site 967 down to 3.2 Ma. This record strongly correlates with runoff in the Sahara and Sahel regions, whereas correlation with the dust record of Site 659 is moderate and slightly improves after NH ice sheet inception. We investigated the transient variability of the individual and combined contributions of the Sahel and Sahara regions and found significant transient behaviour overlapping the inception of NH ice sheets (2.8 Ma) and the Plio-Pleistocene transition (2.6 Ma). Prior to 2.8 Ma, a larger contribution from the Sahara region is required to explain the variability of Mediterranean dust input. After this transition, we found that a more equal contribution of the two regions is required, representing an increased influence of Sahel runoff and wet periods