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Introduction:The majority of pediatric medications are dosed according to weight and therefore accurate weight assessment is essential. However, this can be difficult in the unpredictable and peripatetic prehospital care setting, and medication errors are common. The Handtevy method and the Broselow tape are two systems designed to guide Emergency Medical Services (EMS) providers in both pediatric patient weight estimation and medication dosing. The accuracy of the Handtevy method of weight estimation as practiced in the field by EMS has not been previously examined.Study Objective:The primary objective of this study was to examine the field performance of the Handtevy method and the Broselow tape with respect to prehospital patient weight estimation.Methods:This was a retrospective chart review of trauma and non-trauma patients transported by EMS to the emergency department (ED) of a quaternary care children’s hospital from January 1, 2021 through June 30, 2021. Demographic data, ED visit information, prehospital weight estimation, and medication dosing were collected and analyzed. Scale-based weight from the ED was used as the standard for comparison.Results:A total of 509 patients Conclusion:This study demonstrated no statistically significant difference between the use of the Handtevy or Broselow methods with respect to prehospital weight estimation. While further research is necessary, these results suggest similar field performance of the Broselow and Handtevy methods.

The appropriate duration of dual antiplatelet therapy in patients at high risk for bleeding after the implantation of a drug-eluting coronary stent remains unclear.One month after they had undergone implantation of a biodegradable-polymer sirolimus-eluting coronary stent, we randomly assigned patients at high bleeding risk to discontinue dual antiplatelet therapy immediately (abbreviated therapy) or to continue it for at least 2 additional months (standard therapy). The three ranked primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding; cumulative incidences were assessed at 335 days. The first two outcomes were assessed for noninferiority in the per-protocol population, and the third outcome for superiority in the intention-to-treat population.Among the 4434 patients in the per-protocol population, net adverse clinical events occurred in 165 patients (7.5%) in the abbreviated-therapy group and in 172 (7.7%) in the standard-therapy group (difference, -0.23 percentage points; 95% confidence interval [CI], -1.80 to 1.33; P0.001 for noninferiority). A total of 133 patients (6.1%) in the abbreviated-therapy group and 132 patients (5.9%) in the standard-therapy group had a major adverse cardiac or cerebral event (difference, 0.11 percentage points; 95% CI, -1.29 to 1.51; P = 0.001 for noninferiority). Among the 4579 patients in the intention-to-treat population, major or clinically relevant nonmajor bleeding occurred in 148 patients (6.5%) in the abbreviated-therapy group and in 211 (9.4%) in the standard-therapy group (difference, -2.82 percentage points; 95% CI, -4.40 to -1.24; P0.001 for superiority).One month of dual antiplatelet therapy was noninferior to the continuation of therapy for at least 2 additional months with regard to the occurrence of net adverse clinical events and major adverse cardiac or cerebral events; abbreviated therapy also resulted in a lower incidence of major or clinically relevant nonmajor bleeding. (Funded by Terumo; MASTER DAPT ClinicalTrials.gov number, NCT03023020.).

BACKGROUND Breast arterial calcification (BAC) is a common incidental finding on screening mammography. Recent evidence suggests that BAC is associated with cardiovascular disease (CVD). We systematically reviewed the associations between BAC and reproductive factors (menopausal status, hormone replacement therapy [HRT] use, oral contraceptive [OC] use and parity). METHODS MEDLINE and EMBASE databases, references of relevant papers and Web of Science were searched up to February 2020 for English-language studies that evaluated these associations. Study quality were determined and a random effects model was used to assess these associations. RESULTS Nineteen observational studies (n = 47,249; three cohort studies, seven case-control studies, nine cross-sectional studies) were included. BAC was associated with menopause (nine studies; n = 15,870; odds ratio [OR] 2.67; 95% confidence interval [CI] 1.50-4.77) and parity (seven studies; n = 27,728; OR 2.50; 95% CI 1.68-3.71) and inversely with HRT use (10 studies; n = 33,156; OR 0.57; 95% CI 0.40-0.80). No association was found with OC use. Eleven studies were considered good in quality. Marked heterogeneity existed across all analyses. CONCLUSIONS BAC is associated with HRT use, menopause and parity. However, careful interpretation is required as marked heterogeneity existed across all analyses. Traditional cardiovascular risk factors may need to be taken into account in future investigations of associations between BAC and reproductive factors. PROSPERO CRD42020141644.

Supplemental Digital Content is available in the text., Background: The optimal duration of antiplatelet therapy (APT) in patients at high bleeding risk with or without oral anticoagulation (OAC) after coronary stenting remains unclear. Methods: In the investigator-initiated, randomize, open-label MASTER DAPT trial (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Standard DAPT Regimen), 4579 patients at high bleeding risk were randomized after 1-month dual APT to abbreviated or nonabbreviated APT strategies. Randomization was stratified by concomitant OAC indication. In this subgroup analysis, we report outcomes of populations with or without an OAC indication. In the population with an OAC indication, patients changed immediately to single APT for 5 months (abbreviated regimen) or continued ≥2 months of dual APT and single APT thereafter (nonabbreviated regimen). Patients without an OAC indication changed to single APT for 11 months (abbreviated regimen) or continued ≥5 months of dual APT and single APT thereafter (nonabbreviated regimen). Coprimary outcomes at 335 days after randomization were net adverse clinical outcomes (composite of all-cause death, myocardial infarction, stroke, and Bleeding Academic Research Consortium 3 or 5 bleeding events); major adverse cardiac and cerebral events (all-cause death, myocardial infarction, and stroke); and type 2, 3, or 5 Bleeding Academic Research Consortium bleeding. Results: Net adverse clinical outcomes or major adverse cardiac and cerebral events did not differ with abbreviated versus nonabbreviated APT regimens in patients with OAC indication (n=1666; hazard ratio [HR], 0.83 [95% CI, 0.60–1.15]; and HR, 0.88 [95% CI, 0.60–1.30], respectively) or without OAC indication (n=2913; HR, 1.01 [95% CI, 0.77–1.33]; or HR, 1.06 [95% CI, 0.79–1.44]; Pinteraction=0.35 and 0.45, respectively). Bleeding Academic Research Consortium 2, 3, or 5 bleeding did not significantly differ in patients with OAC indication (HR, 0.83 [95% CI, 0.62–1.12]) but was lower with abbreviated APT in patients without OAC indication (HR, 0.55 [95% CI, 0.41–0.74]; Pinteraction=0.057). The difference in bleeding in patients without OAC indication was driven mainly by a reduction in Bleeding Academic Research Consortium 2 bleedings (HR, 0.48 [95% CI, 0.33–0.69]; Pinteraction=0.021). Conclusions: Rates of net adverse clinical outcomes and major adverse cardiac and cerebral events did not differ with abbreviated APT in patients with high bleeding risk with or without an OAC indication and resulted in lower bleeding rates in patients without an OAC indication. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03023020.

S-Adenosyl-L-methionine (SAM) is an important intracellular metabolite and widely used for treatment of various diseases. Although high level production of SAM had been achieved in yeast, novel metabolic engineering strategies are needed to further enhance SAM production for industrial applications. Here genome-scale engineering (GSE) was performed to identify new targets for SAM overproduction using the multi-functional genome-wide CRISPR (MAGIC) system, and the effects of these newly identified targets were further validated in industrial yeast strains. After 3 rounds of FACS screening and characterization, numerous novel targets for enhancing SAM production were identified. In addition, transcriptomic and metabolomic analyses were performed to investigate the molecular mechanisms for enhanced SAM accumulation. The best combination (upregulation of SNZ3, RFC4, and RPS18B) improved SAM productivity by 2.2-fold and 1.6-fold in laboratory and industrial yeast strains, respectively. Using GSE of laboratory yeast strains to guide industrial yeast strain engineering presents an effective approach to design microbial cell factories for industrial applications.

PurposeReal-time location sensing (RTLS) systems offer a significant potential to advance the management of construction processes by potentially providing real-time access to the locations of workers and equipment. Many location-sensing technologies tend to perform poorly for indoor work environments and generate large data sets that are somewhat difficult to process in a meaningful way. Unfortunately, little is still known regarding the practical benefits of converting raw worker tracking data into meaningful information about construction project progress, effectively impeding widespread adoption in construction.Design/methodology/approachThe presented framework is designed to automate as many steps as possible, aiming to avoid manual procedures that significantly increase the time between progress estimation updates. The authors apply simple location tracking sensor data that does not require personal handling, to ensure continuous data acquisition. They use a generic and non-site-specific knowledge base (KB) created through domain expert interviews. The sensor data and KB are analyzed in an abductive reasoning framework implemented in Answer Set Programming (extended to support spatial and temporal reasoning), a logic programming paradigm developed within the artificial intelligence domain.FindingsThis work demonstrates how abductive reasoning can be applied to automatically generate rich and qualitative information about activities that have been carried out on a construction site. These activities are subsequently used for reasoning about the progress of the construction project. Our framework delivers an upper bound on project progress (“optimistic estimates”) within a practical amount of time, in the order of seconds. The target user group is construction management by providing project planning decision support.Research limitations/implicationsThe KB developed for this early-stage research does not encapsulate an exhaustive body of domain expert knowledge. Instead, it consists of excerpts of activities in the analyzed construction site. The KB is developed to be non-site-specific, but it is not validated as the performed experiments were carried out on one single construction site.Practical implicationsThe presented work enables automated processing of simple location tracking sensor data, which provides construction management with detailed insight into construction site progress without performing labor-intensive procedures common nowadays.Originality/valueWhile automated progress estimation and activity recognition in construction have been studied for some time, the authors approach it differently. Instead of expensive equipment, manually acquired, information-rich sensor data, the authors apply simple data, domain knowledge and a logical reasoning system for which the results are promising.

Introduction:Stingray envenomation is a marine injury suffered by ocean goers throughout the world. No prospective studies exist on the various outcomes associated with these injuries.Study Objective:The aim of this study was to perform a prospective, observational study of human stingray injuries to determine the natural history, acute and subacute complications, prevalence of medical evaluation, and categories of medical treatment.Methods:This study prospectively studied a population of subjects who were injured by stingrays at Seal Beach, California (USA) from July 2012 through September 2016 and did not immediately seek emergency department evaluation. Subjects described their initial injury and provided information on their symptoms, medical evaluations, and medical treatment for the injury at one week and one month after the injury. This information was reported as descriptive statistics.Results:A total of 393 participants were enrolled in the study; 313 (80%) of those completed the one-week follow-up interview and 279 (71%) participants completed both the one-week and one-month follow-up interviews. Overall, 234 (75%) injuries occurred to the foot. One hundred sixty-three (52%) patients had complete resolution of their pain within one week and 261 (94%) had either complete resolution or improvement of pain by one month. Sixty-eight (22%) subjects reported being evaluated by a physician and a total of 49 (17%) subjects reported antibiotic treatment for their wound. None of the subjects required parenteral antibiotics or hospital admission.Conclusion:The majority of stingray victims recover from stingray injury without requiring antibiotics. A subset of subjects will have on-going wound pain after one month. The need for parenteral antibiotics or hospital admission is rare.

There is currently no treatment for attenuating progression of arterial calcification. 18F-sodium fluoride positron emission tomography (18F-NaF PET) locates regions of calcification activity. We tested whether vitamin-K1 or colchicine affected arterial calcification activity. 154 patients with diabetes mellitus and coronary calcification, as detected using computed tomography (CT), were randomized to one of four treatment groups (placebo/placebo, vitamin-K1 [10 mg/day]/placebo, colchicine [0.5 mg/day]/placebo, vitamin-K1 [10 mg/day]/ colchicine [0.5 mg/day]) in a double-blind, placebo-controlled 2x2 factorial trial of three months duration. Change in coronary calcification activity was estimated as a change in coronary maximum tissue-to-background ratio (TBRmax) on 18F-NaF PET. 149 subjects completed follow-up (vitamin-K1: placebo = 73:76 and colchicine: placebo = 73:76). Neither vitamin-K1 nor colchicine had a statistically significant effect on the coronary TBRmax compared with placebo (mean difference for treatment groups 0·00 ± 0·16 and 0·01 ± 0·17, respectively, p > 0.05). There were no serious adverse effects reported with colchicine or vitamin-K1. In patients with type 2 diabetes, neither vitamin-K1 nor colchicine significantly decreases coronary calcification activity, as estimated by 18F-NaF PET, over a period of 3 months. Clinical trial registration: ACTRN12616000024448.

ObjectiveWe tested the hypothesis that patients with a potential acute coronary syndrome (ACS) and very low levels of high-sensitivity cardiac troponin I can be efficiently and safely discharged from the emergency department after a single troponin measurement.MethodsThis prospective cohort study recruited 2255 consecutive patients aged ≥18 years presenting to the Emergency Department, Royal Perth Hospital, Western Australia, with chest pain without high-risk features but requiring the exclusion of ACS. Patients were managed using a guideline-recommended pathway or our novel Single Troponin Accelerated Triage (STAT) pathway. The primary outcome was the percentage of patients discharged in ResultsThe study enrolled 1131 patients to the standard cohort and 1124 to the STAT cohort. Thirty-eight per cent of the standard cohort were discharged directly from emergency department compared with 63% of the STAT cohort (pConclusionsAmong low-risk patients with a potential ACS, a pathway which incorporates early discharge based on a single very low level of high-sensitivity cardiac troponin increases the proportion of patients discharged directly from the emergency department, reduces length of stay and is safe.Trial registration numberACTRN12618000797279.

Purpose of review Elevated lipoprotein(a) [Lp(a)] is a genetic trait that indicates higher risk of atherosclerotic cardiovascular disease (ASCVD). We review novel strategies to mitigate behavioural risk-factors in this genetic condition. Recent findings Pharmacological and biological interventions are available for lowering Lp(a). However, the acceptability and feasibility of these approaches are questionable due to cost and lack of clinical evidence for their efficacy. A number of low-cost, minimal patient contact interventions are available for modifying behavioural risk-factors that are associated with increased risk of ASCVD familial hypercholesterolaemia and diabetes. These include lifestyle interventions designed to improve diet and physical activity. These interventions may be particularly important among individuals with elevated Lp(a) to manage their higher risk of diabetes and ASCVD. The following article outlines recent research that has examined such low-cost, minimal patient contact interventions. Summary The current research indicated that such interventions, which are grounded in psychological theory, can assist individuals to improve their diet and physical activity. These findings have implications for developing and implementing similar interventions for individuals with elevated Lp(a), so as to assist in reducing behavioural risk-factors associated with ASCVD.

Isovist analysis has been typically applied for the study of human perception in indoor built-up spaces. Albeit predominantly in 2D, recent works have explored isovist techniques in 3D. However, 3D applications of isovist analysis simply extrapolate the assumptions of its 2D counterpart, without questioning whether these assumptions remain valid in 3D. They do not: because human perception is embodied, the perception of vertical space differs from the perception of horizontal space. We present a user study demonstrating that an embodied 3D isovist that accounts for this phenomenon (formalised based on the notion of spatial artefacts) predicts human perception of space more accurately than the generic volumetric 3D isovist, specifically with respect to spaciousness and complexity. We suggest that the embodied 3D isovist should be used for 3D analyses in which human perception is of key interest.

Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH.We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis.We studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M- group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p0.05), in the M+ compared with the M- group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p0.05), but not in the left circumflex.Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques.

BACKGROUND Nonadherence to antiplatelet therapy after percutaneous coronary intervention (PCI) is common, even in clinical trials. OBJECTIVES The purpose of this study was to investigate the impact of nonadherence to study protocol regimens in the MASTER DAPT (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen) trial. METHODS At 1-month after PCI, 4,579 high bleeding risk patients were randomized to single antiplatelet therapy (SAPT) for 11 months (or 5 months in patients on oral anticoagulation [OAC]) or dual antiplatelet therapy (DAPT) for ≥2 months followed by SAPT. Coprimary outcomes included net adverse clinical events (NACE), major adverse cardiac and cerebral events (MACE), and major or clinically relevant nonmajor bleeding (MCB) at 335 days. Inverse probability-of-censoring weights were used to correct for nonadherence Academic Research Consortium type 2 or 3. RESULTS In total, 464 (20.2%) patients in the abbreviated-treatment and 214 (9.4%) in the standard-treatment groups incurred nonadherence Academic Research Consortium type 2 or 3. At inverse probability-of-censoring weights analyses, NACE (HR: 1.01; 95% CI: 0.88-1.27) or MACE (HR: 1.07; 95% CI: 0.83-1.40) did not differ, and MCB was lower with abbreviated compared with standard treatment (HR: 0.51; 95% CI: 0.60-0.73) consistently across OAC subgroups; among OAC patients, SAPT discontinuation 6 months after PCI was associated with similar MACE and lower MCB (HR: 0.47; 95% CI: 0.22-0.99) compared with SAPT continuation. CONCLUSIONS In the MASTER DAPT adherent population, 1-month compared with ≥3-month DAPT was associated with similar NACE or MACE and lower MCB. Among OAC patients, SAPT discontinuation after 6 months was associated with similar MACE and lower MCB than SAPT continuation (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen [MASTER DAPT]; NCT03023020).

The transition to a fully-fledged circular economy (CE) has proven to be challenging for many industries. Despite possible competitive advantages of moving industries towards CE activities, their practical implementation is still limited. This communication article delivers ad interim an identification of technological challenges and opportunities for the European plastics industries to facilitate circularity ambitions. In applying the qualitative-empirical Gioia-method utilizing the GABEK-WinRelan tool, specific technological challenges and opportunities for plastics industries were identified. Major findings indicate that technological challenges for plastics are predominantly seen in (C1) secondary material contamination; (C2) recycling processing issues; (C3) production processing issues; (C4) production material quality issues; and (C5) end-product quality issues, while the opportunities lie in (O1) effective secondary material management; (O2) innovation for chemical recycling; (O3) innovation for production and processability; (O4) innovative materials; and (O5) innovative end-products. This article contributes to the contemporary debate of CE challenges and opportunities to plastics valorization by highlighting the promising role of chemical recycling on a monomer-level as a key facilitator to a circular plastics economy. Further, it was found that technological transitions must be coupled with compatible market incentive mechanisms guided by effective institutional structures.

Rhodotorula toruloides has been increasingly explored as a host for bioproduction of lipids, fatty acid derivatives and terpenoids. Various genetic tools have been developed, but neither a centromere nor an autonomously replicating sequence (ARS), both necessary elements for stable episomal plasmid maintenance, has yet been reported. In this study, cleavage under targets and release using nuclease (CUT&RUN), a method used for genome-wide mapping of DNA–protein interactions, was used to identify R. toruloides IFO0880 genomic regions associated with the centromeric histone H3 protein Cse4, a marker of centromeric DNA. Fifteen putative centromeres ranging from 8 to 19 kb in length were identified and analyzed, and four were tested for, but did not show, ARS activity. These centromeric sequences contained below average GC content, corresponded to transcriptional cold spots, were primarily nonrepetitive and shared some vestigial transposon-related sequences but otherwise did not show significant sequence conservation. Future efforts to identify an ARS in this yeast can utilize these centromeric DNA sequences to improve the stability of episomal plasmids derived from putative ARS elements.

Background Endothelial shear stress (ESS) has a critical role in endothelial function. Abnormal shear stress leads to endothelial dysfunction, which contributes to arterial plaque initiation and development. Four dimensional magnetic resonance can determine shear stress in the larger arteries but cannot resolve the detail needed to calculate shear stress in the coronary arteries and thus methods such as computational fluid dynamics (CFD) are required. Additionally, a key feature of biologically active plaques is microcalcification activity, and this can be detected using 18F-sodium fluoride (18F-NaF) positron emission tomography (PET). Furthermore, using high resolution optical coherence tomography (OCT), the high-risk features plaques can be visualized and quantified. We aimed to merge these three techniques to investigate if low ESS is associated with high-risk plaque features and active microcalcifications in acute coronary syndrome. Methods We began by merging OCT images with CTCA images to obtain detailed 3D reconstructions of the target vessel. We then simulated blood flow and calculated the ESS, from which we extracted the area of low ESS ( Results We investigated 20 arteries from 18 patients which we obtained 38 coronary segments according to the SCCT guidelines. We found that areas of low ESS were were significantly and positively associated with high-risk plaque features: macrophage infiltration (segment, rs=0.33, p=0.043; artery, rs=0.46, p=0.041) and presence of cholesterol crystals (segment, rs=0.45, p=0.005; artery, rs=0.58, p=0.007). Vessel segments with thin-capped fibroatheroma had greater area of low ESS (20 vs 4%). The uptake of 18F-NaF was positively associated with the area of low ESS (segment, rs=0.52, p=0.001; artery, rs=0.64, p=0.002). We found that there were typically more plaque features found in regions of low ESS (Table 1). Conclusion Here we provide the first data associating low ESS with both high-risk plaque features and active microcalcifications in patients with acute coronary syndrome. Although our sample size is small, these data are encouraging and could lead to better understanding of how best to deem a plaque “high risk”. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Royal Perth Hospital Medical Research Foundation Figure 1Table 1

Background Physiological assessment of intermediate coronary artery lesions to guide therapy is well established. Recently, the use of non-hyperaemic pressure ratios (NHPRs) has been suggested as a reliable alternative to hyperaemic assessment, such as fractional flow reserve (FFR). However certain patient / lesion subsets, including proximal lesion location, young patient age and assessment of non-LAD vessels, have been associated with discordance of resting and hyperaemic measurements which has led to some confusion over their interpretation and integration into routine clinical practice. Purpose To evaluate the frequency of discordant resting and hyperaemic measurements among patients undergoing assessment of intermediate coronary artery stenoses, and to identify common lesion-specific features within patients with discordant data. Methods From our coronary physiology database, we identified consecutive lesions which had been assessed between October 2020 and March 2021 with both resting (resting full-cycle ratio; RFR) and hyperaemic (wire-based FFR with peripheral adenosine) indices. Positive RFR defined as 0.93, grey zone RFR 0.89–0.93). Positive FFR defined as Results 100 lesions were identified as being assessed with both RFR and FFR, in 83 patients (67% male), mean age 67 (±12) years, vessel assessed; LAD 66, RCA 19, LCx 13, LMCA 1 and radial graft 1; with 45 being proximal lesions. 30 RFR measurements were in the grey zone. Of the remaining 70 lesions, 55 results (79%) were concordant (Group 2 = 31, Group 3 = 24), with 15 results (21%) being discordant (Group 1 = 3, Group 4 = 12). Negative predictive value (NPV) of RFR (for FFR Conclusion Overall within our patient group, there appeared to be a good association of RFR to FFR. In particular, RFR had a high NPV for an FFR Funding Acknowledgement Type of funding sources: None.

Background The oleaginous, carotenogenic yeast Rhodotorula toruloides has been increasingly explored as a platform organism for the production of terpenoids and fatty acid derivatives. Fatty alcohols, a fatty acid derivative widely used in the production of detergents and surfactants, can be produced microbially with the expression of a heterologous fatty acyl-CoA reductase. Due to its high lipid production, R. toruloides has high potential for fatty alcohol production, and in this study several metabolic engineering approaches were investigated to improve the titer of this product. Results Fatty acyl-CoA reductase from Marinobacter aqueolei was co-expressed with SpCas9 in R. toruloides IFO0880 and a panel of gene overexpressions and Cas9-mediated gene deletions were explored to increase the fatty alcohol production. Two overexpression targets (ACL1 and ACC1, improving cytosolic acetyl-CoA and malonyl-CoA production, respectively) and two deletion targets (the acyltransferases DGA1 and LRO1) resulted in significant (1.8 to 4.4-fold) increases to the fatty alcohol titer in culture tubes. Combinatorial exploration of these modifications in bioreactor fermentation culminated in a 3.7 g/L fatty alcohol titer in the LRO1Δ mutant. As LRO1 deletion was not found to be beneficial for fatty alcohol production in other yeasts, a lipidomic comparison of the DGA1 and LRO1 knockout mutants was performed, finding that DGA1 is the primary acyltransferase responsible for triacylglyceride production in R. toruloides, while LRO1 disruption simultaneously improved fatty alcohol production, increased diacylglyceride and triacylglyceride production, and increased glucose consumption. Conclusions The fatty alcohol titer of fatty acyl-CoA reductase-expressing R. toruloides was significantly improved through the deletion of LRO1, or the deletion of DGA1 combined with overexpression of ACC1 and ACL1. Disruption of LRO1 surprisingly increased both lipid and fatty alcohol production, creating a possible avenue for future study of the lipid metabolism of this yeast.

Business model innovation for sustainability (BMIfS) has recently seen a surge in academia and practice. This article introduces an ordonomic BMIfS meta-framework to further stimulate the growing research interest on how available approaches to tensions in BMIfS can be purposefully reconciled to improve the management of BMIfS. The ordonomic BMIfS meta-framework proposes an opportunity to mediate between the normative desiderata of integrative approaches and ‘practical’ instrumental ones to tensions, which feature prominently in the contemporary literature. Within this meta-framework, both approaches play equally important but categorially different roles. This article contributes by proposing to actively shape the ‘boundary conditions’ in BMIfS processes to prevent tensions manifesting in irreconcilable tradeoffs.

A fundamental challenge within the field of renovation is handling enormous complexity at two levels. Firstly, complexity at the level of an individual building project must be handled that consists of thousands of building elements that are amenable to renovation, and how each renovation action impacts a range of competing key performance indicators (KPIs), which are unique for every project. Secondly, complexity must be handled at the AECO-community level of knowledge about what renovation actions are available today. The aims of this paper are first to present an innovative approach for addressing these challenges through developing a Renovation Domain Model for expressing and capturing key concepts for renovation scenarios; and second to propose an innovative renovation design support framework that provides design teams with broad coverage of the design space in conjunction with limited, careful use of precise simulations for KPI evaluation. The system is empirically evaluated on a large residential building case study in Denmark.

The oleaginous yeast Rhodosporidium toruloides is considered a promising candidate for production of chemicals and biofuels thanks to its ability to grow on lignocellulosic biomass, and its high production of lipids and carotenoids. However, efforts to engineer this organism are hindered by a lack of suitable genetic tools. Here we report the development of a CRISPR/Cas9 system for genome editing in R. toruloides based on a fusion 5S rRNA-tRNA promoter for guide RNA (gRNA) expression, capable of greater than 95% gene knockout for various genetic targets. Additionally, multiplexed double-gene knockout mutants were obtained using this method with an efficiency of 78%. This tool can be used to accelerate future metabolic engineering work in this yeast.

Reported associations between vitamin K1 and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52–60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K1 (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87–192 µg/d) intake of vitamin K1 was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K1 intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K1 may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00806-9.

Background Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET). Objectives We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus. Methods This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta. Results In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002). Conclusions In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448.

Purpose of review Diabetes mellitus is no longer considered a cardiovascular disease (CVD) risk equivalent, but the optimal methods of risk stratification are a matter of debate. The coronary calcium score (CCS) is a measure of the burden of atherosclerosis and is widely used for CVD risk stratification in the general population. We review recently published data to describe the role of the CCS in people with diabetes mellitus. Recent findings People with diabetes mellitus have 10-year event rates for CVD and CVD mortality that are considered high, at a much lower level of CCS than the general population. Different categories of CCS are pertinent to men and women with diabetes mellitus. CCS may be particularly useful in clinical settings when CVD risk is known to be increased but difficult to quantify, for example peri-menopausal women, young persons with diabetes, type 1 diabetic individuals and others. With modern techniques, the radiation dose of a CSS has fallen to levels wherein screening and surveillance could be considered. Summary The CCS is able to quantify CVD risk in people with diabetes mellitus when there is clinical uncertainty and identifies those with very high event rates. Future research should aim to identify effective risk reduction strategies in this important group.

Civil engineering has only recently started the digitalisation journey by standardising around Building Information Models (BIMs). In the process of construction a dimension of time is added in what is called 4D BIM and this can serve as the basis for a digital twin. It is predicted that such a digital twin can enhance the overall overview of status of the construction of a new building by means of different types of sensors, and interpreting these in relation to a BIM. In the construction phase there are rules and regulations targeting the safety of the different kinds of construction workers at the construction site. In this paper we provide a vision of how digital twins can assist with spotting potential violations of the constraints stated by the rules and regulations, and empirically evaluate a proof-of-concept software tool on a large scale, real-world 4D BIM.

Objective: The coronary calcium score (CCS) predicts cardiovascular disease risk in individuals with diabetes mellitus, and rate of progression of CCS is an additional and incremental marker of risk. 18 F-sodium fluoride positron emission tomography ( 18 F-NaF PET) detects early and active calcifications within the vasculature. We aimed to ascertain the relationship between 18 F-NaF PET activity and CCS progression in patients with diabetes mellitus. Approach and Results: We identified individuals between 50 and 80 years with diabetes mellitus and no history of clinical coronary artery disease. Those with a CCS ≥10 were invited to undergo 18 F-NaF PET scanning and then repeat CCS >2 years later. 18 F-NaF PET and CCS analysis were performed on a per-coronary and a per-patient level. We compared the proportion of CCS progressors in 18 F-NaF PET–positive versus 18 F-NaF PET–negative coronary arteries. Forty-one participants with 163 coronary arteries underwent follow-up CCS 2.8±0.5 years later. 18 F-NaF PET–positive coronary arteries (n=52) were more likely to be CCS progressors, compared with negative coronary arteries (n=111; 86.5% versus 52.3%, P 18 F-NaF PET–positive disease was an independent predictor of subsequent CCS progression (odds ratio, 2.92 [95% CI, 1.32–6.45], P =0.008). All subjects (100%, 15/15) with ≥2 18 F-NaF–positive coronary arteries progressed in CCS. Conclusions: In subjects with diabetes mellitus, 18 F-NaF PET positivity at baseline, independently predicted the progression of calcifications within the coronary arteries 2.8 years later. These findings suggest 18 F-NaF PET may be a promising technique for earlier identification of patients at higher risk of cardiovascular events.

Background The rate of increase of coronary arterial calcification score (CCS) on serial CT-scans years apart is a potent marker of cardiovascular risk but identifies risk only after irreversible damage has occurred. Molecular imaging may assist in identifying patients who are at risk of developing severe arterial calcification. Purpose To determine if 18F-Sodium Fluoride Positron Emission Tomography (18F-NaF PET) can predict and anatomically locate the progression of CCS over 2 years. Methods Subjects with diabetes mellitus underwent a baseline 18F-NaF PET scan and a CT CCS. The CT CCS was repeated after 2 years. 18F-NaF PET tracer uptake was measured as the maximum tissue to background ratio (TBRmax) and using a pre-defined cut-off for positivity, arteries were dichotomised into 18F-NaF positive and negative. We compared the change in the CCS between coronary arteries that were positive and negative for 18F-NaF uptake. Results In forty-one participants (mean age 65.0±7.1, male: 63.4%) a total of 163 coronary arteries were included in the analysis. Fifty-two (31.9%) coronary arteries were 18F-NaF positive at baseline and 111 (68.1%) were negative. After 2.8 [2.4–3.2] years follow-up, the TBRmax at baseline correlated with the time-standardised change in the CCS (Spearmans' rho 0.33, p Conclusions 18F-NaF PET activity at baseline is associated with new co-localised calcifications 2.8 years later Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Royal Perth Hospital Research Foundation

We present a new approach based on spatial reasoning in Answer Set Programming (ASP), and a prototype software tool, for automatically evaluating construction safety compliance of real-world Building Information Models (BIM) that have both a geometric component and temporal component in the form of a construction plan and schedule (4D BIM). In the 4D BIM domain, geometries of building objects are large and complex making it highly impractical to represent geometries as ASP facts, unoptimised spatial reasoning can be prohibitively slow, and rounding errors in floating point arithmetic often result in logical contradictions. Our novel framework addresses these challenges by integrating a specialised geometry database, built-in spatial optimisations, and support for real arithmetic solving. We empirically evaluate our prototype software tool on two large 4D BIM models from real buildings to demonstrate the practicality and scalability of our new framework to real-world workplace hazard prevention tasks in construction safety-in-design analysis.

The segmentation and analysis of coronary arteries from intravascular optical coherence tomography (IVOCT) is an important aspect of diagnosing and managing coronary artery disease. Current image processing methods are hindered by the time needed to generate expert-labelled datasets and the potential for bias during the analysis. Therefore, automated, robust, unbiased and timely geometry extraction from IVOCT, using image processing, would be beneficial to clinicians. With clinical application in mind, we aim to develop a model with a small memory footprint that is fast at inference time without sacrificing segmentation quality. Using a large IVOCT dataset of 12,011 expert-labelled images from 22 patients, we construct a new deep learning method based on capsules which automatically produces lumen segmentations. Our dataset contains images with both blood and light artefacts (22.8%), as well as metallic (23.1%) and bioresorbable stents (2.5%). We split the dataset into a training (70%), validation (20%) and test (10%) set and rigorously investigate design variations with respect to upsampling regimes and input selection. We show that our developments lead to a model, DeepCap, that is on par with state-of-the-art machine learning methods in terms of segmentation quality and robustness, while using as little as 12% of the parameters. This enables DeepCap to have per image inference times up to 70% faster on GPU and up to 95% faster on CPU compared to other state-of-the-art models. DeepCap is a robust automated segmentation tool that can aid clinicians to extract unbiased geometrical data from IVOCT., Comment: This version has been accepted in Artificial Intelligence in Medicine. Main paper: 28 pages, 9 figures, 4 tables. Supplementary Material: 3 pages, 3 figures

Sustainable building renovation design is a highly challenging and ever more pressing issue in the construction sector. Architects must search through a large number of potential designs while aiming to optimize a range of Key Performance Indicators (KPIs) that measure, for example, construction cost, energy efficiency, an occupant’s sense of privacy, and so on.

Non-model microorganisms have been increasingly explored as microbial cell factories for production of chemicals, fuels, and materials owing to their unique physiology and metabolic capabilities. However, these microorganisms often lack facile genetic tools for strain development, which hinders their adoption as production hosts. In this review, we describe recent advances in domestication of non-model microorganisms, including bacteria, actinobacteria, cyanobacteria, yeast, and fungi, with a focus on the development of genetic tools. In addition, we highlight some successful applications of non-model microorganisms as microbial cell factories.

Lipoprotein(a) [Lp(a)] and diabetes are independently associated with premature coronary artery disease (pCAD). However, there is an inverse relationship between Lp(a) concentration and type 2 diabetes (T2D) risk. We examine whether Lp(a) distribution in patients with pCAD differs between those with or without T2D, and whether elevated Lp(a) is associated with pCAD in patients with T2D.Lp(a) concentration was measured in consecutive acute coronary syndrome (ACS) patients in two coronary care units (study one: ACS with or without diabetes, study two: ACS and diabetes). Elevated Lp(a) mass concentration was defined as ≥0.5 g/L and pCAD where CAD was diagnosed age60 years. The association between elevated Lp(a) and pCAD was assessed using logistic regression.Of 449 patients, 233 (51.9%) had pCAD and 278 (61.9%) had T2D. In patients with pCAD, those with T2D had a significantly lower median Lp(a) concentration (0.13 g/L versus 0.27 g/L, p=0.004). In patients with T2D, elevated Lp(a) was significantly associated with pCAD (OR 2.419, 95% CI 1.513-3.867, p0.001). After adjusting for gender, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, elevated Lp(a) remained significantly associated with pCAD (OR 2.895, 95% CI 1.427-5.876, p=0.003) in patients with T2D.In coronary care patients with pCAD, patients with T2D had lower Lp(a) concentrations than those without T2D. Despite this, elevated Lp(a) remained predictive of pCAD in patients with T2D. Measurement of Lp(a) should be considered in younger adults with T2D to identify who may benefit from earlier preventative therapies to reduce pCAD burden.

Cardiovascular disease is the leading cause of death and disability worldwide. Recent work suggests a link between vitamin K insufficiency and deficiency with vascular calcification, a marker of advanced atherosclerosis. Vitamin K refers to a group of fat-soluble vitamins important for blood coagulation, reducing inflammation, regulating blood calcium metabolism, as well as bone metabolism, all of which may play a role in promoting cardiovascular health. Presently, there is a lack of a comprehensive vitamin K database on individual foods, which are required to accurately calculate vitamin K1 and K2 intake for examination in epidemiological studies. This has likely contributed to ambiguity regarding the recommended daily intake of vitamin K, including whether vitamin K1 and K2 may have separate, partly overlapping functions. This review will discuss the presence of: (i) vitamin K1 and K2 in the diet; (ii) the methods of quantitating vitamin K compounds in foods; and (iii) provide an overview of the evidence for the cardiovascular health benefits of vitamin K in observational and clinical trials.

The Department of Engineering at Aarhus University has started up a new science-based BSc degree in Computer Engineering. We report about our planning of the curriculum during the first two years in the Software Engineering area. We discuss highlights, basic concepts, selected course contents, inter and intra course progression, observations from the first two semesters taught, and our expectations concerning the learning objectives and outcomes of the curriculum as a whole.

Background The ascending aorta is an uncommon site for non-infective mural thrombus. The detection of such a thrombus is of particular importance, given the risk of systemic and coronary embolisation. We present a case of a 60-year-old female with an ascending aortic thrombus complicated by non-ST-elevation myocardial infarction (NSTEMI), and associated systemic embolism in the form of renal and splenic infarcts. Case Report A 60-year-old female was admitted to a local secondary hospital with a 4-day history of crampy abdominal pain and intermittent bilateral arm pain associated with nausea and vomiting. Past medical history included known hypertrophic cardiomyopathy, gastroesophageal reflux disease, carpal tunnel syndrome, hepatic steatosis, but no known thrombophilia or coronary artery disease. Computer tomography (CT) scan of the abdomen revealed subacute infarction of the right kidney and spleen in keeping with a thrombo-embolic event. A CT pulmonary angiogram revealed a small pulmonary embolus in the right lower lobe. Troponin I level was elevated at 11 mg/L (normal After discussion with the multidisciplinary Heart team, the consensus was that the aortic mass was likely thrombus formation relating to erosion of aortic atheroma. It was hypothesised that this may have resulted in distal embolisation to the left kidney and spleen, and possibly also caused embolisation to the LAD artery, although the cause of the pulmonary embolism was still unknown. The patient was then discharged on rivaroxaban and aspirin. A repeat transoesophageal echocardiogram was performed 4 months after discharge to assess the ascending aortic mass. It showed complete resolution of the mass in the ascending aorta, with no change in any other cardiac structures. Discussion Although thrombus formation is uncommon in the ascending aorta, certain conditions, such as pregnancy and thrombophilia increase its risk. Several case reports of ascending aortic thrombus were found in the literature, but this will be the first to report complete resolution with treatment using a direct oral anticoagulant. Abstract 480 Figure. Ascending Aortic Thrombus + Resolution

Specific occupational construction safety, health, and well-being related knowledge and information are scattered and fragmented. Despite technological advancements of information and knowledge management, a link between safety management and information models is still missing. In this paper we present first steps towards a unifying formal (logic-based) domain model of construction safety, called SafeConDM, that consists of: (1) a semantically rich ontology of hazard, safety concepts, and concept relationships that builds on, and integrates with, existing construction safety ontologies and building information models; (2) a set of first-order if-then rules linking construction site states with the potential for specific hazards to occur that we define in a novel way using spatial artefacts. We present a prototype software tool, based on our ASP4BIM tool that implements SafeConDM for construction hazard analysis and safe construction planning decision support, and empirically evaluate our tool on three real-world construction building models.