Aetiology and predictors of major bleeding events in patients with heart failure with reduced ejection fraction undergoing percutaneous coronary intervention.

OBJECTIVES: We sought to determine the relationship between the degree of left ventricular ejection fraction (LVEF) impairment and the frequency and type of bleeding events after percutaneous coronary intervention (PCI). DESIGN: This was an observational retrospective cohort analysis. Patients who underwent PCI from 2009 to 2017 were identified from our institutional National Cardiovascular Disease Registry (NCDR) CathPCI database. Patients were stratified by pre-PCI LVEF: preserved (≥50%), mildly reduced (41%-49%) and reduced (≤40%) LVEF. PRIMARY OUTCOME MEASURES: The outcome was major bleeding, defined by NCDR criteria. Events were classified based on bleeding aetiology and analysed by multivariable logistic regression. RESULTS: Among 13 537 PCIs, there were 817 bleeding events (6%). The rate of bleeding due to any cause, blood transfusion, gastrointestinal bleeding and coronary artery perforation or tamponade each increased in a stepwise fashion comparing preserved, mildly reduced and reduced LVEF reduction (p<0.05 for all comparisons). However, there were no differences in bleeding due to asymptomatic drops in haemoglobin, access site haematoma or retroperitoneal bleeding. After multivariable adjustment, mildly reduced and reduced LVEF remained independent predictors of bleeding events (OR 1.36, 95% CI 1.06 to 1.74, p<0.05 and OR 1.73, 95% CI 1.45 to 2.06, p<0.0001). CONCLUSIONS: The degree of LV dysfunction is an independent predictor of post-PCI major bleeding events. Patients with mildly reduced or reduced LVEF are at greatest risk of post-PCI bleeding, driven by an increased need for blood transfusion, major GI bleeding events and coronary artery perforation or tamponade. Pre-PCI LV dysfunction does not predict asymptomatic declines in haemoglobin, access site haematoma or retroperitoneal bleeding.

Tight-packing of large pilin subunits provides distinct structural and mechanical properties for the Myxococcus xanthus type IVa pilus.

Type IVa pili (T4aP) are ubiquitous cell surface filaments important for surface motility, adhesion to surfaces, DNA uptake, biofilm formation, and virulence. T4aP are built from thousands of copies of the major pilin subunit and tipped by a complex composed of minor pilins and in some systems also the PilY1 adhesin. While major pilins of structurally characterized T4aP have lengths of <165 residues, the major pilin PilA of Myxococcus xanthus is unusually large with 208 residues. All major pilins have a conserved N-terminal domain and a variable C-terminal domain, and the additional residues of PilA are due to a larger C-terminal domain. We solved the structure of the M. xanthus T4aP (T4aPMx) at a resolution of 3.0 Å using cryo-EM. The T4aPMx follows the structural blueprint of other T4aP with the pilus core comprised of the interacting N-terminal α1-helices, while the globular domains decorate the T4aP surface. The atomic model of PilA built into this map shows that the large C-terminal domain has more extensive intersubunit contacts than major pilins in other T4aP. As expected from these greater contacts, the bending and axial stiffness of the T4aPMx is significantly higher than that of other T4aP and supports T4aP-dependent motility on surfaces of different stiffnesses. Notably, T4aPMx variants with interrupted intersubunit interfaces had decreased bending stiffness, pilus length, and strongly reduced motility. These observations support an evolutionary scenario whereby the large major pilin enables the formation of a rigid T4aP that expands the environmental conditions in which the T4aP system functions.

Near-atomic-resolution structure of J-aggregated helical light-harvesting nanotubes.

Cryo-electron microscopy has delivered a resolution revolution for biological self-assemblies, yet only a handful of structures have been solved for synthetic supramolecular materials. Particularly for chromophore supramolecular aggregates, high-resolution structures are necessary for understanding and modulating the long-range excitonic coupling. Here, we present a 3.3 Å structure of prototypical biomimetic light-harvesting nanotubes derived from an amphiphilic cyanine dye (C8S3-Cl). Helical 3D reconstruction directly visualizes the chromophore packing that controls the excitonic properties. Our structure clearly shows a brick layer arrangement, revising the previously hypothesized herringbone arrangement. Furthermore, we identify a new non-biological supramolecular motif-interlocking sulfonates-that may be responsible for the slip-stacked packing and J-aggregate nature of the light-harvesting nanotubes. This work shows how independently obtained native-state structures complement photophysical measurements and will enable accurate understanding of (excitonic) structure-function properties, informing materials design for light-harvesting chromophore aggregates.

Large pilin subunits provide distinct structural and mechanical properties for the Myxococcus xanthus type IV pilus.

Type IV pili (T4P) are ubiquitous bacterial cell surface filaments important for surface motility, adhesion to biotic and abiotic surfaces, DNA uptake, biofilm formation, and virulence. T4P are built from thousands of copies of the major pilin subunit and tipped by a complex composed of minor pilins and in some systems also the PilY1 adhesin. While the major pilins of structurally characterized T4P have lengths of up to 161 residues, the major pilin PilA of Myxococcus xanthus is unusually large with 208 residues. All major pilins have a highly conserved N-terminal domain and a highly variable C-terminal domain, and the additional residues in the M. xanthus PilA are due to a larger C-terminal domain. We solved the structure of the M. xanthus T4P (T4P Mx ) at a resolution of 3.0 Å using cryo-electron microscopy (cryo-EM). The T4P Mx follows the structural blueprint observed in other T4P with the pilus core comprised of the extensively interacting N-terminal α1-helices while the globular domains decorate the T4P surface. The atomic model of PilA built into this map shows that the large C-terminal domain has much more extensive intersubunit contacts than major pilins in other T4P. As expected from these greater contacts, the bending and axial stiffness of the T4P Mx is significantly higher than that of other T4P and supports T4P-dependent motility on surfaces of different stiffnesses. Notably, T4P Mx variants with interrupted intersubunit interfaces had decreased bending stiffness and strongly reduced motility on all surfaces. These observations support an evolutionary scenario whereby the large major pilin enables the formation of a rigid T4P that expands the environmental conditions in which the T4P system functions.

Introduce a rotational robust optimization framework for spot-scanning proton arc (SPArc) therapy.

Objective. Proton dosimetric uncertainties resulting from the patient's daily setup errors in rotational directions exist even with advanced image-guided radiotherapy techniques. Thus, we developed a new rotational robust optimization SPArc algorithm (SPArcrot) to mitigate the dosimetric impact of the rotational setup error in Raystation ver. 6.02 (RaySearch Laboratory AB, Stockholm, Sweden).Approach.The initial planning CT was rotated ±5° simulating the worst-case setup error in the roll direction. The SPArcrotuses a multi-CT robust optimization framework by taking into account of such rotational setup errors. Five cases representing different disease sites were evaluated. Both SPArcoriginaland SPArcrotplans were generated using the same translational robust optimized parameters. To quantitatively investigate the mitigation effect from the rotational setup errors, all plans were recalculated using a series of pseudo-CT with rotational setup error (±1°/±2°/±3°/±5°). Dosimetric metrics such as D98% of CTV, and 3D gamma analysis were used to assess the dose distribution changes in the target and OARs.Main results.The magnitudes of dosimetric changes in the targets due to rotational setup error were significantly reduced by the SPArcrotcompared to SPArc in all cases. The uncertainties of the max dose to the OARs, such as brainstem, spinal cord and esophagus were significantly reduced using SPArcrot. The uncertainties of the mean dose to the OARs such as liver and oral cavity, parotid were comparable between the two planning techniques. The gamma passing rate (3%/3 mm) was significantly improved for CTV of all tumor sites through SPArcrot.Significance.Rotational setup error is one of the major issues which could lead to significant dose perturbations. SPArcrotplanning approach can consider such rotational error from patient setup or gantry rotation error by effectively mitigating the dose uncertainties to the target and in the adjunct series OARs.

Convergent evolution in the supercoiling of prokaryotic flagellar filaments.

The supercoiling of bacterial and archaeal flagellar filaments is required for motility. Archaeal flagellar filaments have no homology to their bacterial counterparts and are instead homologs of bacterial type IV pili. How these prokaryotic flagellar filaments, each composed of thousands of copies of identical subunits, can form stable supercoils under torsional stress is a fascinating puzzle for which structural insights have been elusive. Advances in cryoelectron microscopy (cryo-EM) make it now possible to directly visualize the basis for supercoiling, and here, we show the atomic structures of supercoiled bacterial and archaeal flagellar filaments. For the bacterial flagellar filament, we identify 11 distinct protofilament conformations with three broad classes of inter-protomer interface. For the archaeal flagellar filament, 10 protofilaments form a supercoil geometry supported by 10 distinct conformations, with one inter-protomer discontinuity creating a seam inside of the curve. Our results suggest that convergent evolution has yielded stable superhelical geometries that enable microbial locomotion.

Susceptibility weighted MRI pinpoints spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats.

PURPOSE: To find magnetic resonance imaging (MRI) precursors of spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats (SHRSP). METHOD: SHRSP rats were used with both a low/high salt (n = 18 or 11) Japanese diet and salty drinking water to generate spontaneous intracerebral hemorrhage (ICH). Various MRI sequences, and in particular, susceptibility weighted imaging (SWI), were used and combined with a gadolinium (Gd) contrast agent or oxygen gas to identify the rupture of the blood brain barrier (BBB) and the temporal ICH. RESULTS: Most rats developed hypertensive ICH stroke in the high salt group during the 10-13 week period compared to only one third of rats in the low salt group during the 14-18 week period. The location of stroke for both the low/high-salt groups was highest in the striatum (58%/43%), followed by the cortex (21%/30%). The edematous enhancement on T2 weighted (T2W) imaging or Gd based T1 weighted (Gd-T1W) imaging due to the ruptured BBB preceded the striatal hemorrhages seen on SWI. The most recent bleeds were observed on temporal SWI or on oxygen-enhanced SWI. The mode of the volume of bleeds was 0.4 mm3. A positive correlation between susceptibility x volume and R2* x volume of the bleeds was observed. CONCLUSIONS: SHRSP rats with the high salt diet effectively generated a hypertensive hemorrhagic stroke which could be monitored by various MRI sequences. The venous dilation on SWI may precede any abnormality on T2W or Gd-T1W imaging. The edematous enhancement on T2W or Gd-T1W indicated a BBB breakdown that may precede striatal ICH by several days. This suggests the need for immediate treatment to improve outcome if this finding is observed. The use of oxygen with SWI was able to help differentiate old bleeds from very recent bleeds.

miR-3934 regulates the apoptosis and secretion of inflammatory cytokines of basophils via targeting RAGE in asthma.

BACKGROUND: Several miRNAs are now known to have clear connections to the pathogenesis of asthma. The present study focused on the potential role of miR-3934 during asthma development. METHODS: miR-3934 was detected as a down-regulated miRNA in basophils by sequencing analysis. Next, the expression levels of miR-3934 in peripheral blood mononuclear cells of 50 asthma patients and 50 healthy volunteers were examined by RT-qPCR methods. The basophils were then treated with AGEs and transfected with miR-3934 mimics. The apoptosis levels were examined by flow cytometry assay; and the expression levels of cytokines were detected using the ELISA kits. Finally, the Western blot was performed to examined the expression of key molecules in the TGF-ß/Smad signaling pathway. RESULTS: miR-3934 was down-regulated in the basophils of asthmatic patients. The expression of the pro-inflammatory cytokines IL-6, IL-8 and IL-33 was enhanced in basophils from asthmatic patients, and this effect was partially reversed by transfection of miR-3934 mimics. Furthermore, receiver operating characteristics analysis showed that miR-3934 levels can be used to distinguish asthma patients from healthy individuals. miR-3934 partially inhibited advanced glycation end products-induced increases in basophil apoptosis by suppressing expression of RAGE. CONCLUSION: Our results indicate that miR-3934 acts to mitigate the pathogenesis of asthma by targeting RAGE and suppressing TGF-ß/Smad signaling.

Development of Risk Prediction Model for Muscular Calf Vein Thrombosis with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Purpose: This study aims to establish a risk prediction model for muscular calf vein thrombosis (MCVT) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: The research sample consisted of 248 patients with AECOPD and all of them underwent vascular ultrasounds of both lower limbs in this retrospective study. Univariate analysis and multivariate logistic regression analysis were conducted on factors with significant group differences to screen for the independent risk factors of MCVT. A nomogram to predict the risk of MCVT was constructed and validated with bootstrap resampling. Results: According to the exclusion criteria, 240 patients were included for analysis, divided into the MCVT group (n = 81) and the non-MCVT group (n = 159). Multivariate logistic regression analyses showed that hypertension, elevated MPV, reduced albumin (ALB), elevated D-dimer and bed rest ≥3 days were independent risk factors for MCVT in AECOPD. A nomogram model for predicting AECOPD with MCVT was established based on them. The area under the curve (AUC) of receiver operating characteristic (ROC) curve for the prediction model and the simplified Wells score was 0.784 (95% CI: 0.722-0.847) and 0.659 (95% CI: 0.583-0.735), respectively. The cut-off value and Youden index of prediction model were 0.248 and 0.454, respectively. At the same time, the sensitivity, specificity, positive predictive value, and negative predictive value of the prediction model were 85.9%, 59.5%, 84.6%, and 77.4%, respectively. The sensitivity and specificity of the simplified Wells score were 67.9% and 56.3%, respectively. Validation by the use of bootstrap resampling revealed optimal discrimination and calibration, and the decision analysis curve (DAC) suggested that this prediction model involved high clinical practicability. Conclusion: We developed a nomogram that can predict the risk of MCVT for AECOPD patients. This model has the potential to assist clinicians in making treatment recommendations and formulating corresponding prevention measures.

Photorhabdus luminescens TccC3 Toxin Targets the Dynamic Population of F-Actin and Impairs Cell Cortex Integrity.

Due to its essential role in cellular processes, actin is a common target for bacterial toxins. One such toxin, TccC3, is an effector domain of the ABC-toxin produced by entomopathogenic bacteria of Photorhabdus spp. Unlike other actin-targeting toxins, TccC3 uniquely ADP-ribosylates actin at Thr-148, resulting in the formation of actin aggregates and inhibition of phagocytosis. It has been shown that the fully modified F-actin is resistant to depolymerization by cofilin and gelsolin, but their effects on partially modified actin were not explored. We found that only F-actin unprotected by tropomyosin is the physiological TccC3 substrate. Yet, ADP-ribosylated G-actin can be produced upon cofilin-accelerated F-actin depolymerization, which was only mildly inhibited in partially modified actin. The affinity of TccC3-ADP-ribosylated G-actin for profilin and thymosin-ß4 was weakened moderately but sufficiently to potentiate spontaneous polymerization in their presence. Interestingly, the Arp2/3-mediated nucleation was also potentiated by T148-ADP-ribosylation. Notably, even partially modified actin showed reduced bundling by plastins and α-actinin. In agreement with the role of these and other tandem calponin-homology domain actin organizers in the assembly of the cortical actin network, TccC3 induced intense membrane blebbing in cultured cells. Overall, our data suggest that TccC3 imposes a complex action on the cytoskeleton by affecting F-actin nucleation, recycling, and interaction with actin-binding proteins involved in the integration of actin filaments with each other and cellular elements.

Redefine the Role of Spot-Scanning Proton Beam Therapy for the Single Brain Metastasis Stereotactic Radiosurgery.

Purpose: To explore the role of using Pencil Beam Scanning (PBS) proton beam therapy in single lesion brain stereotactic radiosurgery (SRS), we developed and validated a dosimetric in silico model to assist in the selection of an optimal treatment approach among the conventional Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Proton Therapy (IMPT) and Spot-scanning Proton Arc (SPArc). Material and Methods: A patient's head CT data set was used as an in silico model. A series of targets (volume range from 0.3 cc to 33.03 cc) were inserted in the deep central and peripheral region, simulating targets with different sizes and locations. Three planning groups: IMPT, VMAT, and SPArc were created for dosimetric comparison purposes and a decision tree was built based on this in silico model. Nine patients with single brain metastases were retrospectively selected for validation. Multiple dosimetric metrics were analyzed to assess the plan quality, such as dose Conformity Index (CI) (ratio of the target volume to 100% prescription isodose volume); R50 (ratio of 50% prescription isodose volume to the target volume); V12Gy (volume of brain tissue minus GTV receiving 12 Gy), and mean dose of the normal brain. Normal tissue complication probability (NTCP) of brain radionecrosis (RN) was calculated using the Lyman-Kutcher-Burman (LKB) model and total treatment delivery time was calculated. Six physicians from different institutions participated in the blind survey to evaluate the plan quality and rank their choices. Results: The study showed that SPArc has a dosimetric advantage in the V12Gy and R50 with target volumes > 9.00 cc compared to VMAT and IMPT. A significant clinical benefit can be found in deep centrally located lesions larger than 20.00 cc using SPArc because of the superior dose conformity and mean dose reduction in healthy brain tissue. Nine retrospective clinical cases and the blind survey showed good agreement with the in silico dosimetric model and decision tree. Additionally, SPArc significantly reduced the treatment delivery time compared to VMAT (SPArc 184.46 ± 59.51s vs. VMAT: 1574.78 ± 213.65s). Conclusion: The study demonstrated the feasibility of using Proton beam therapy for single brain metastasis patients utilizing the SPArc technique. At the current stage of technological development, VMAT remains the current standard modality of choice for single lesion brain SRS. The in silico dosimetric model and decision tree presented here could be used as a practical clinical decision tool to assist the selection of the optimal treatment modality among VMAT, IMPT, and SPArc in centers that have both photon and proton capabilities.

Clinical Application and Evaluation of Metagenomic Next-Generation Sequencing in Pulmonary Infection with Pleural Effusion.

Purpose: Metagenomic next-generation sequencing (mNGS) is a novel technique of pathogens detection that plays an increasingly important role in clinical practice. In this study, we explored the application value of mNGS in pulmonary infection combined with pleural effusion applied to samples of pleural effusion fluid. Patients and Methods: We reviewed 80 cases of pulmonary infection with pleural effusion between August 2020 and October 2021. Among them, 40 patients were placed in the mNGS group and underwent both culture and mNGS testing; the patients in the control group were only subjected to culture test. The effectiveness of mNGS was evaluated for microbial composition and diagnostic accuracy in every pleural effusion specimen type. Results: We found that the positive rate of mNGS was 70% (28/40). The comparison between mNGS and culture method resulted that the sensitivity was 100% (95% CI: 29.2-100%) and the specificity was 64.9% (95% CI: 47.5-79.8%). The positive predictive value of mNGS was 18.8% (95% CI, 13.0-26.3%), and the negative predictive value was 100%. The most commonly identified potential pathogens were bacteria, such as Streptococcus, Prevotella, Parvimonas, Porphyromonas and Gemella. The most detected fungal infection was Candida and Pneumocystis. A total of 11 patients were identified as mixed infection by mNGS. Treatment regimen adjustments were made according to mNGS results and the overall length of hospital stay in the mNGS group was shorter compared to that of the control group. Conclusion: In this study, mNGS produced higher positive rates than the culture method in detecting pathogens in the pleural effusion specimens. The technology performed satisfactorily, providing more diagnostic evidence and reducing the length of hospital stay.

Allosteric regulation controls actin-bundling properties of human plastins.

Plastins/fimbrins are conserved actin-bundling proteins contributing to motility, cytokinesis and other cellular processes by organizing strikingly different actin assemblies as in aligned bundles and branched networks. We propose that this ability of human plastins stems from an allosteric communication between their actin-binding domains (ABD1/2) engaged in a tight spatial association. Here we show that ABD2 can bind actin three orders of magnitude stronger than ABD1, unless the domains are involved in an equally strong inhibitory engagement. A mutation mimicking physiologically relevant phosphorylation at the ABD1-ABD2 interface greatly weakened their association, dramatically potentiating actin cross-linking. Cryo-EM reconstruction revealed the ABD1-actin interface and enabled modeling of the plastin bridge and domain separation in parallel bundles. We predict that a strong and tunable allosteric inhibition between the domains allows plastins to modulate the cross-linking strength, contributing to remodeling of actin assemblies of different morphologies defining the unique place of plastins in actin organization.

Developing an accurate model of spot-scanning treatment delivery time and sequence for a compact superconducting synchrocyclotron proton therapy system.

BACKGROUND: A new compact superconducting synchrocyclotron single-room proton solution delivers pulsed proton beams to each spot through several irradiation bursts calculated by an iterative layer delivery algorithm. Such a mechanism results in a new beam parameter, burst switching time (BST) in the total beam delivery time (BDT) which has never been studied before. In this study, we propose an experimental approach to build an accurate BDT and sequence prediction model for this new proton solution. METHODS: Test fields and clinical treatment plans were used to investigate each beam delivery parameter that impacted BDT. The machine delivery log files were retrospectively analyzed to quantitatively model energy layer switching time (ELST), spot switching time (SSWT), spot spill time (SSPT), and BST. A total of 102 clinical IMPT treatment fields' log files were processed to validate the accuracy of the BDT prediction model in comparison with the result from the current commercial system. Interplay effect is also investigated as a clinical application by comparing this new delivery system model with a conventional cyclotron accelerator model. RESULTS: The study finds that BST depends on the amount of data to be transmitted between two sequential radiation bursts, including a machine irradiation log file of the previous burst and a command file to instruct the proton system to deliver the next burst. The 102 clinical treatment fields showed that the accuracy of each component of the BDT matches well between machine log files and BDT prediction model. More specifically, the difference of ELST, SSWT, SSPT, and BST were (- 3.1 ± 5.7)%, (5.9 ± 3.9)%, (2.6 ± 8.7)%, and (- 2.3 ± 5.3)%, respectively. The average total BDT was about (2.1 ± 3.0)% difference compared to the treatment log files, which was significantly improved from the current commercial proton system prediction (58 ± 15)%. Compared to the conventional cyclotron system, the burst technique from synchrocyclotron effectively reduced the interplay effect in mobile tumor treatment. CONCLUSION: An accurate BDT and sequence prediction model was established for this new clinical compact superconducting synchrocyclotron single-room proton solution. Its application could help users of similar facilities better assess the interplay effect and estimate daily patient treatment throughput.

Expression profiling of N6-methyladenosine modified circRNAs in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, associated with poor prognosis and easy relapse of disease. Circular RNAs (circRNAs) were detected to be m6A modified and the role of m6A circRNAs has been reported in other diseases including cancers, however, their role has not been elucidated in AML yet. In the present study, we aimed to investigate the expression profiling of m6A circRNAs in AML. We performed m6A circRNAs microarray analysis to identify differentially expressed m6A circRNAs in bone marrow samples from AML patients and healthy individuals (control). Furthermore, bioinformatics analysis predicted the potential functions and relevant pathways that may be associated with the m6A circRNAs. The circRNA m6A methylation levels were found to be positively associated with the circRNAs expression, suggesting circRNA m6A modification could contribute to circRNA regulation in AML. Further analysis demonstrated that circRNA m6A modification might influence the circRNA-miRNA-mRNA co-expression network that may contribute to the circRNA regulatory network in AML. Our findings provide evidence of the differential expression profile of m6A circRNAs in AML, and circRNA m6A modification may contribute to circRNA regulatory function in AML.

Quantifying the contribution of lipoprotein(a) to all apoB containing particles.

BACKGROUND: Elevated lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). As clinical LDL cholesterol [LDL-C] incorporates cholesterol from Lp(a) [Lp(a)-C], there is interest in quantifying the contribution of Lp(a)-C to LDL-C given implications for risk assessment, diagnosis, and treatment. Estimating Lp(a)-C is subject to inaccuracies; measuring Lp(a) particle number [Lp(a)-P] is more accurate. OBJECTIVE: To capture how Lp(a) contributes to the concentration of atherogenic particles, we demonstrate a particle-based approach using readily available measures of Lp(a)-P and apolipoprotein B (apoB). METHODS: Using the Very Large Database of Lipids (VLDbL), we compared Lp(a)-P (nmol/L) with all apoB containing particles ("apoB-P"). apoB-P was calculated by converting apoB mass to molar concentration using the preserved molecular weight of apoB100 (512 kg/mol). We calculated the percentage of Lp(a)-P relative to apoB-P by Lp(a)-P deciles and stratified by triglycerides, LDL-C, and non-HDL-C. RESULTS: 158,260 patients from the VLDbL were included. The fraction Lp(a)-P/apoB-P increased with rising Lp(a)-P. Lp(a)-P comprised on average 3% of apoB containing particles among the study population and 15% at the highest Lp(a)-P decile. Lp(a)-P/apoB-P decreased at higher levels of triglycerides and LDL-C owing to larger contributions from VLDL and LDL. CONCLUSIONS: We demonstrate a particle-based approach to quantify the contribution of Lp(a) to all apoB-containing particles using validated and widely available clinical assays. This approach keeps in line with recommendations to move away from mass-based measurements of Lp(a) and prioritize more accurate particle-based measurements. Future research applying this method could define clinically meaningful thresholds and inform use in risk assessment and management.

Assessing the Accuracy of Estimated Lipoprotein(a) Cholesterol and Lipoprotein(a)-Free Low-Density Lipoprotein Cholesterol.

Background Accurate measurement of the cholesterol within lipoprotein(a) (Lp[a]-C) and its contribution to low-density lipoprotein cholesterol (LDL-C) has important implications for risk assessment, diagnosis, and treatment of atherosclerotic cardiovascular disease, as well as in familial hypercholesterolemia. A method for estimating Lp(a)-C from particle number using fixed conversion factors has been proposed (Lp[a]-C from particle number divided by 2.4 for Lp(a) mass, multiplied by 30% for Lp[a]-C). The accuracy of this method, which theoretically can isolate "Lp(a)-free LDL-C," has not been validated. Methods and Results In 177 875 patients from the VLDbL (Very Large Database of Lipids), we compared estimated Lp(a)-C and Lp(a)-free LDL-C with measured values and quantified absolute and percent error. We compared findings with an analogous data set from the Mayo Clinic Laboratory. Error in estimated Lp(a)-C and Lp(a)-free LDL-C increased with higher Lp(a)-C values. Median error for estimated Lp(a)-C <10 mg/dL was -1.9 mg/dL (interquartile range, -4.0 to 0.2); this error increased linearly, overestimating by +30.8 mg/dL (interquartile range, 26.1-36.5) for estimated Lp(a)-C ≥50 mg/dL. This error relationship persisted after stratification by overall high-density lipoprotein cholesterol and high-density lipoprotein cholesterol subtypes. Similar findings were observed in the Mayo cohort. Absolute error for Lp(a)-free LDL-C was +2.4 (interquartile range, -0.6 to 5.3) for Lp(a)-C<10 mg/dL and -31.8 (interquartile range, -37.8 to -26.5) mg/dL for Lp(a)-C≥50 mg/dL. Conclusions Lp(a)-C estimations using fixed conversion factors overestimated Lp(a)-C and subsequently underestimated Lp(a)-free LDL-C, especially at clinically relevant Lp(a) values. Application of inaccurate Lp(a)-C estimations to correct LDL-C may lead to undertreatment of high-risk patients.

Building a precise machine-specific time structure of the spot and energy delivery model for a cyclotron-based proton therapy system.

Objective. We proposed an experimental approach to build a precise machine-specific beam delivery time (BDT) prediction and delivery sequence model for standard, volumetric, and layer repainting delivery based on a cyclotron accelerator system.Approach. Test fields and clinical treatment plans' log files were used to experimentally derive three main beam delivery parameters that impacted BDT: energy layer switching time (ELST), spot switching time, and spot drill time. This derived machine-specific model includes standard, volumetric, and layer repainting delivery sequences. A total of 103 clinical treatment fields were used to validate the model.Main results. The study found that ELST is not stochastic in this specific machine. Instead, it is actually the data transmission time or energy selection time, whichever takes longer. The validation showed that the accuracy of each component of the BDT matches well between machine log files and the model's prediction. The average total BDT was about (-0.74 ± 3.33)% difference compared to the actual treatment log files, which is improved from the current commercial proton therapy system's prediction (67.22%±26.19%).Significance. An accurate BDT prediction and delivery sequence model was established for an cyclotron-based proton therapy system IBA ProteusPLUS®. Most institutions could adopt this method to build a machine-specific model for their own proton system.