Massive Parallelization of Massive Sample-size Survival Analysis.

Large-scale observational health databases are increasingly popular for conducting comparative effectiveness and safety studies of medical products. However, increasing number of patients poses computational challenges when fitting survival regression models in such studies. In this paper, we use graphics processing units (GPUs) to parallelize the computational bottlenecks of massive sample-size survival analyses. Specifically, we develop and apply time- and memory-efficient single-pass parallel scan algorithms for Cox proportional hazards models and forward-backward parallel scan algorithms for Fine-Gray models for analysis with and without a competing risk using a cyclic coordinate descent optimization approach. We demonstrate that GPUs accelerate the computation of fitting these complex models in large databases by orders of magnitude as compared to traditional multi-core CPU parallelism. Our implementation enables efficient large-scale observational studies involving millions of patients and thousands of patient characteristics. The above implementation is available in the open-source R package Cyclops (Suchard et al., 2013).

Understanding the Molecular Arrangement and Orientation Characteristics of Mesophase Pitch and Its Fibers via a Polarized Light Microscope.

A polarized light microscope (PLM) was utilized to examine the optical textures of mesophase pitch (MP) and MP-derived fibers, which aimed to reveal the arrangement and orientation characteristics of pitch molecules and to clarify the evolution and transformation mechanism of carbonaceous microcrystalline from pitch fibers to graphitized fibers. The results found that there were distinct optical textures in MP, where one side exhibited a transition from a flattening plane to a mountain-like undulating plane. This transition corresponded to the arrangement of pitch molecules, resembling stacked lamellar structures reminiscent of curved paper. Meanwhile, the optical textures of fibers revealed that the blue substance was wrapped around the red grain-like domains in the longitudinal section and confirmed that the red part belonged to the pyridine insoluble fraction of MP and the blue part belonged to its pyridine-soluble fraction. After graphitization, the red part was transformed into graphite sheets and the blue part was transformed into an amorphous carbon layer which was wrapped around the graphite sheets, forming a carbonaceous microcrystalline package-like bag. Therefore, this study provided a comprehensive interpretation of the structural evolution mechanism of MP and MP-derived fibers based on their macro-optical textures and micro-nanostructures.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Multinational patterns of second line antihyperglycaemic drug initiation across cardiovascular risk groups: federated pharmacoepidemiological evaluation in LEGEND-T2DM.

Objective: To assess the uptake of second line antihyperglycaemic drugs among patients with type 2 diabetes mellitus who are receiving metformin. Design: Federated pharmacoepidemiological evaluation in LEGEND-T2DM. Setting: 10 US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network in eight countries from 2011 to the end of 2021. Participants: 4.8 million patients (≥18 years) across US and non-US based databases with type 2 diabetes mellitus who had received metformin monotherapy and had initiated second line treatments. Exposure: The exposure used to evaluate each database was calendar year trends, with the years in the study that were specific to each cohort. Main outcomes measures: The outcome was the incidence of second line antihyperglycaemic drug use (ie, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas) among individuals who were already receiving treatment with metformin. The relative drug class level uptake across cardiovascular risk groups was also evaluated. Results: 4.6 million patients were identified in US databases, 61 382 from Spain, 32 442 from Germany, 25 173 from the UK, 13 270 from France, 5580 from Scotland, 4614 from Hong Kong, and 2322 from Australia. During 2011-21, the combined proportional initiation of the cardioprotective antihyperglycaemic drugs (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) increased across all data sources, with the combined initiation of these drugs as second line drugs in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors increased more significantly among populations with no cardiovascular disease compared with patients with established cardiovascular disease. No data source provided evidence of a greater increase in the uptake of these two drug classes in populations with cardiovascular disease compared with no cardiovascular disease. Conclusions: Despite the increase in overall uptake of cardioprotective antihyperglycaemic drugs as second line treatments for type 2 diabetes mellitus, their uptake was lower in patients with cardiovascular disease than in people with no cardiovascular disease over the past decade. A strategy is needed to ensure that medication use is concordant with guideline recommendations to improve outcomes of patients with type 2 diabetes mellitus.

Eco-Friendly Preparation of Carbon-Bonded Carbon Fiber Based on Glucose-Polyacrylamide Hydrogel Derived Carbon as Binder.

Lightweight, high-temperature-resistant carbon-bonded carbon fiber (CBCF) composites with excellent thermal insulation properties are desirable materials for thermal protection systems in military and aerospace applications. Here, glucose was introduced into the polyacrylamide hydrogel to form the glucose-polyacrylamide (Glu-PAM) hydrogel. The CBCF composites were prepared using the Glu-PAM hydrogel as a brand-new binder, and the synergistic effect between glucose and acrylamide was investigated. The results showed the Glu-PAM hydrogel could limit the foaming of glucose and enhance the carbon yield of glucose. Meanwhile, the dopamine-modified chopped carbon fiber could be uniformly mixed by high-speed shearing to form a slurry with the Glu-PAM hydrogel. Finally, the slurry was successfully extruded and molded to prepare CBCF composites with a density of 0.158~0.390 g cm-3 and excellent thermal insulation performance and good mechanical properties. The compressive strength of CBCF composites with a density of 0.158 g cm-3 in the Z direction is 0.18 MPa, and the thermal conductivity in the Z direction at 25 °C and 1200 °C is 0.10 W m-1 k-1 and 0.20 W m-1 k-1, respectively. This study provided an efficient, environment-friendly, and cost-effective strategy for the preparation of CBCF composites.

In-Situ Doping B4C Nanoparticles in Mesophase Pitch for Preparing Carbon Fibers with High Thermal Conductivity by Boron Catalytic Graphitization.

The boron carbide (B4C) nanoparticles doping mesophase pitch (MP) was synthesized by the in-situ doping method with tetrahydrofuran solvent, and the corresponding MP-based carbon fibers (CFs) were successfully prepared through the melt-spinning, stabilization, carbonization and graphitization processes. The structural evolution and properties of boron-containing pitches and fibers in different processes were investigated for exploring the effect of B4C on mechanical, electrical and thermal properties of CFs. The results showed that the B4C was evenly dispersed in pitch fibers to provide active sites of oxygen, resulting in a homogeneous stabilization and ameliorating the split-ting microstructures of CFs. Moreover, the thermal conductivity of B1-MP-CF prepared with 1 wt.% B4C increased to 1051 W/m•K, which was much higher than that of B0-MP-CF prepared without B4C (659 W/m•K). While the tensile strength of B4C-doped CFs was lower than that of pristine CFs. In addition, a linear relationship equation between the graphite microcrystallite parameter (ID/IG) calculated from Raman spectra and the thermal conductivity (λ) calculated according to the electrical resistivity was found, which was beneficial to understand the thermal properties of CFs. Therefore, the doping B4C nanoparticles in MP did play a significant role in reducing the graphitization temperatures due to the boron catalytic graphitization but decreasing the mechanical properties due to the introduction of impurities.

Mesophase Pitch-Based Carbon Fibers: Accelerated Stabilization of Pitch Fibers under Effective Plasma Irradiation-Assisted Modification.

Stabilization is the most complicated and time-consuming step in the manufacture of carbon fibers (CFs), which is important to prepare CFs with high performance. Accelerated stabilization was successfully demonstrated under effective plasma irradiation-assisted modification (PIM) of mesophase pitch fibers (PFs). The results showed that the PIM treatment could obviously introduce more oxygen-containing groups into PFs, which was remarkably efficient in shortening the stabilization time of PFs with a faster stabilization heating rate, as well as in preparing the corresponding CFs with higher performance. The obtained graphitized fiber (GF-5) from the PF-5 under PIM treatment of 5 min presented a higher tensile strength of 2.21 GPa, a higher tensile modulus of 502 GPa, and a higher thermal conductivity of 920 W/m·K compared to other GFs. Therefore, the accelerated stabilization of PFs by PIM treatment is an efficient strategy for developing low-cost pitch-based CFs with high performance.

A Superior Potassium-Ion Anode Material from Pitch-based Activated Carbon Fibers with Hierarchical Pore Structure Prepared by Metal Catalytic Activation.

The pitch-based activated carbon fibers with nickel sulfide nanoparticles (ACF/NiS) were designed by in situ polymerization of ethylene tar with the addition of nickel nitrate followed by melt spinning, stabilization, carbonization, steam activation, and vulcanization processes. The ACF/NiS with hierarchical pore structure and abundant active sites was used as an anode material to improve Coulombic efficiency and increase capacity of potassium-ion batteries (PIBs). The results showed the obtained ACF/NiS with excellent specific surface area of 1552 m2 g-1 and high mesopore volume contribution of 38%, which delivered a high initial Coulombic efficiency of 84.22%, a high capacity of 292.5 mAh g-1, and retained 95.7% capacity retention after 200 cycles at 0.5 A g-1 current density. The NiS provided abundant active sites for the adsorption of potassium-ion, and the rich hierarchical structure shortened the electrolyte penetration path and expanded the storage space of potassium-ion, making it easier to store potassium-ion inside the ACF/NiS anode to obtain a better performance. This work presented one strategy for designing the hierarchical pore structure of pitch-based ACF to boost the capacity storage of PIBs and revealed that ACF-based carbon materials served as potential anodes for high-performance PIBs.

How Confident Are We about Observational Findings in Healthcare: A Benchmark Study.

Healthcare professionals increasingly rely on observational healthcare data, such as administrative claims and electronic health records, to estimate the causal effects of interventions. However, limited prior studies raise concerns about the real-world performance of the statistical and epidemiological methods that are used. We present the "OHDSI Methods Benchmark" that aims to evaluate the performance of effect estimation methods on real data. The benchmark comprises a gold standard, a set of metrics, and a set of open source software tools. The gold standard is a collection of real negative controls (drug-outcome pairs where no causal effect appears to exist) and synthetic positive controls (drug-outcome pairs that augment negative controls with simulated causal effects). We apply the benchmark using four large healthcare databases to evaluate methods commonly used in practice: the new-user cohort, self-controlled cohort, case-control, case-crossover, and self-controlled case series designs. The results confirm the concerns about these methods, showing that for most methods the operating characteristics deviate considerably from nominal levels. For example, in most contexts, only half of the 95% confidence intervals we calculated contain the corresponding true effect size. We previously developed an "empirical calibration" procedure to restore these characteristics and we also evaluate this procedure. While no one method dominates, self-controlled methods such as the empirically calibrated self-controlled case series perform well across a wide range of scenarios.

Comparative safety and effectiveness of alendronate versus raloxifene in women with osteoporosis.

Alendronate and raloxifene are among the most popular anti-osteoporosis medications. However, there is a lack of head-to-head comparative effectiveness studies comparing the two treatments. We conducted a retrospective large-scale multicenter study encompassing over 300 million patients across nine databases encoded in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The primary outcome was the incidence of osteoporotic hip fracture, while secondary outcomes were vertebral fracture, atypical femoral fracture (AFF), osteonecrosis of the jaw (ONJ), and esophageal cancer. We used propensity score trimming and stratification based on an expansive propensity score model with all pre-treatment patient characteritistcs. We accounted for unmeasured confounding using negative control outcomes to estimate and adjust for residual systematic bias in each data source. We identified 283,586 alendronate patients and 40,463 raloxifene patients. There were 7.48 hip fracture, 8.18 vertebral fracture, 1.14 AFF, 0.21 esophageal cancer and 0.09 ONJ events per 1,000 person-years in the alendronate cohort and 6.62, 7.36, 0.69, 0.22 and 0.06 events per 1,000 person-years, respectively, in the raloxifene cohort. Alendronate and raloxifene have a similar hip fracture risk (hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.94-1.13), but alendronate users are more likely to have vertebral fractures (HR 1.07, 95% CI 1.01-1.14). Alendronate has higher risk for AFF (HR 1.51, 95% CI 1.23-1.84) but similar risk for esophageal cancer (HR 0.95, 95% CI 0.53-1.70), and ONJ (HR 1.62, 95% CI 0.78-3.34). We demonstrated substantial control of measured confounding by propensity score adjustment, and minimal residual systematic bias through negative control experiments, lending credibility to our effect estimates. Raloxifene is as effective as alendronate and may remain an option in the prevention of osteoporotic fracture.

Boosting the Potassium-Ion Storage Performance in Soft Carbon Anodes by the Synergistic Effect of Optimized Molten Salt Medium and N/S Dual-Doping.

Soft carbon is attracting tremendous attention as a promising anode material for potassium-ion batteries (PIBs) because of its graphitizable structure and adjustable interlayer distance. Herein, nitrogen/sulfur dual-doped porous soft carbon nanosheets (NSC) have been prepared with coal tar pitch as carbon precursors in an appropriate molten salt medium. The molten salt medium and N/S dual-doping are responsible for the formation of nanosheet-like morphology, abundant microporous channels with a high surface area of 436 m2 g-1, expanded interlamellar spacing of 0.378 nm, and enormous defect-induced active sites. These structural features are crucial for boosting potassium-ion storage performance, endowing the NSC to deliver a high potassiation storage capacity of 359 mAh g-1 at 100 mA g-1 and 115 mAh g-1 at 5.0 A g-1, and retaining 92.4% capacity retention at 1.0 A g-1 after 1000 cycles. More importantly, the pre-intercalation of K atom from the molten salts helps improve the initial Coulombic efficiency to 50%, which outperforms those of the recently reported carbon anode materials with large surface areas. The density functional theory calculations further illuminate that the N/S dual-doping can facilitate the adsorption of K-ion in carbon materials and decrease the ion diffusion energy barrier during the solid-state charge migration.

Ablation Behavior of the SiC-Coated Three-Dimensional Highly Thermal Conductive Mesophase-Pitch-Based Carbon-Fiber-Reinforced Carbon Matrix Composite under Plasma Flame.

This study is focused on a novel high-thermal-conductive C/C composite used in heat-redistribution thermal protection systems. The 3D mesophase pitch-based carbon fiber (CFMP) preform was prepared using CFMP in the X (Y) direction and polyacrylonitrile carbon fiber (CFPAN) in the Z direction. After the preform was densified by chemical vapor infiltration (CVI) and polymer infiltration and pyrolysis (PIP), the 3D high-thermal-conductive C/C (CMP/C) composite was obtained. The prepared CMP/C composite has higher thermal conduction in the X and Y directions. After an ablation test, the CFPAN becomes needle-shaped, while the CFMP shows a wedge shape. The fiber/matrix and matrix/matrix interfaces are preferentially oxidized and damaged during ablation. After being coated by SiC coating, the thermal conductivity plays a significant role in decreasing the hot-side temperature and protecting the SiC coating from erosion by flame. The SiC-coated CMP/C composite has better ablation resistance than the SiC-coated CPAN/C composite. The mass ablation rate of the sample is 0.19 mg·(cm-2·s-1), and the linear ablation rate is 0.52 µm·s-1.

MIL/Aptamer as a Nanosensor Capable of Resisting Nonspecific Displacement for ATP Imaging in Living Cells.

Fluorescent probes physisorbed on nanomaterials have emerged as a kind of useful and facile sensing platform for biological important molecules. However, nonspecific displacement in the physisorption systems is a non-negligible problem for the intracellular analysis. MIL (Materials of Institut Lavoisier), a subclass of metal-organic frameworks (MOFs), has high porosity, large surface area, and intriguing three-dimensional (3D) nanostructure with promising biological and biomedical applications such as molecular detection and drug delivery. Herein, we report MIL/aptamer-FAM as a nanosensor capable of resisting nonspecific displacement for intracellular adenosinetriphosphate (ATP) sensing and imaging. In this approach, by virtue of the remarkable quenching capability, high affinity of aptamers, and dramatic capability of resisting nonspecific displacement of 3D MIL-100, the assay and imaging of ATP in living cells were realized. Our results demonstrated that the MIL/aptamer-FAM nanosensor not only shows high selectivity for the detection of ATP in buffer but also is able to act as a "signal-on" nanosensor for specific imaging of ATP in living cells. The strategy reported here opens up a new way to develop MOF-based nanosensors for intracellular delivery and metabolite detection.

A Comparison of Ethylene-Tar-Derived Isotropic Pitches Prepared by Air Blowing and Nitrogen Distillation Methods and Their Carbon Fibers.

Two isotropic pitches were prepared by air blowing and nitrogen distillation methods using ethylene tar (ET) as a raw material. The corresponding carbon fibers were obtained through conventional melt spinning, stabilization, and carbonization. The structures and properties of the resultant pitches and fibers were characterized, and their differences were examined. The results showed that the introduction of oxygen by the air blowing method could quickly increase the yield and the softening point of the pitch. Moreover, the air-blown pitch (ABP) was composed of aromatic molecules with linear methylene chains, while the nitrogen-distilled pitch (NDP) mainly contained polycondensed aromatic rings. This is because the oxygen-containing functional groups in the ABP could impede ordered stack of pitch molecules and led to a methylene bridge structure instead of an aromatic condensed structure as in the NDP. Meanwhile, the spinnability of the ABP did not decrease even though it contained 2.31 wt % oxygen. In contrast, the ABP had narrower molecular weight distribution, which contributed to better stabilization properties and higher tensile strength of the carbon fiber. The tensile strength of carbon fibers from the ABP reached 860 MPa with fiber diameter of about 10 µm, which was higher than the tensile strength of 640 MPa for the NDP-derived carbon fibers.

KO tBu-Promoted C4 Selective Coupling Reaction of Phenols and [60]Fullerene: One-Pot Synthesis of 4-[60]Fullerephenols under Transition-Metal-Free Conditions.

A KO tBu-promoted direct coupling reaction of phenols and [60]fullerene was disclosed. The reaction occurs exclusively at the C4-position of phenols with high regioselectivity and provides an efficient and inexpensive manner to various 4-[60]fullerephenols in good yields. The electrochemical properties of the products render the method attractive and valuable.

Evolution of Phosphorus-Containing Groups on Activated Carbons during Heat Treatment.

Two types of activated carbons have been prepared by H3PO4 activation of lignocellulose and by H3PO4 modification of activated carbon, and then heat-treated at temperatures from 400 to 900 °C in an atmosphere of N2 or H2 to investigate the evolution of phosphorus-containing groups. Elemental analysis, X-ray photoelectron spectroscopy, 31P nuclear magnetic resonance, nitrogen adsorption, and scanning electron microscopy have been used to analyze the physicochemical properties of the activated carbons. The results show that C-O-P linkages of phosphorus-containing groups can progressively evolve into C-P-O, C3-P═O, C3-P, and eventually elemental phosphorus as a result of heat treatment. Phosphate-like groups are much more thermally stable in an N2 than in an H2 atmosphere. In N2, C-O-P linkages significantly evolve into C-P-O and C3-P═O at up to 800 °C, whereas C3-P linkages are not formed even at 900 °C. In H2, the corresponding evolution remarkably occurs at 500 °C, forming C3-P linkages and eventually elemental phosphorus. Moreover, the two activated carbons exhibit different evolution trends, suggesting that the evolution happens more easily for phosphorus-containing groups located on the edges of graphite-like crystallites than those in the lattice. Finally, we propose different evolution pathways of phosphorus-containing groups upon heat treatment in N2 and H2 atmospheres.