Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G‐computation and inverse‐probability‐weighting, ...have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite‐sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open‐source R package “MedMR.”
Infrared photodetectors based on single‐layer CVD‐grown graphene and PbS quantum dots, which are fabricated by solution processing, show ultrahigh responsivities of up to 107 A/W under infrared light ...illumination. The devices fabricated on flexible plastic substrates have excellent bending stability. The photoresponse is attributed to the field‐effect doping in graphene films induced by negative charges generated in the quantum dots.
We perform a stacking analysis of Planck, AKARI, Infrared Astronomical Satellite, Wide-field Infrared Survey Explorer, and Herschel images of the largest number of (candidate) protoclusters at z ∼ ...3.8 selected from the Hyper Suprime-Cam Subaru Strategic Program. Stacking the images of the 179 candidate protoclusters, the combined infrared (IR) emission of the protocluster galaxies in the observed 12-850 m wavelength range is successfully detected with >5 significance (at Planck). This is the first time that the average IR spectral energy distribution (SED) of a protocluster has been constrained at z ∼ 4. The observed IR SEDs of the protoclusters exhibit significant excess emission in the mid-IR compared to that expected from typical star-forming galaxies (SFGs). They are reproduced well using SED models of intense starburst galaxies with warm/hot dust heated by young stars, or by a population of active galactic nucleus (AGN)/SFG composites. For the pure star-forming model, a total IR (from 8-1000 m) luminosity of 19.3 − 4.2 + 0.6 × 10 13 L and a star formation rate of 16.3 − 7.8 + 1.0 × 10 3 M yr−1 are found, whereas for the AGN/SFG composite model, 5.1 − 2.5 + 2.5 × 10 13 L and 2.1 − 1.7 + 6.3 × 10 3 M yr−1 are found. Uncertainty remains in the total SFRs; however, the IR luminosities of the most massive protoclusters are likely to continue increasing up to z ∼ 4. Meanwhile, no significant IR flux excess is observed around optically selected QSOs at similar redshifts, which confirms previous results. Our results suggest that the z ∼ 4 protoclusters trace dense, intensely star-forming environments that may also host obscured AGNs missed by the selection in the optical.
Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal ...parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two‐way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path‐specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when crossworld exchangeability is invalid. Consequently, this study yields a robustness‐specificity trade‐off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer dataset from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality.
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Achondroplasia is a rare disease affecting bone growth and is caused by a missense mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. In the past few years, there were ...multiple experimental drugs entering into clinical trials for treating achondroplasia including vosoritide, the first precision medicine approved for this indication.
This perspective presents the mechanism of action, benefit, and potential mechanistic limitation of the drugs currently being evaluated in clinical trials for achondroplasia. This article also discusses the potential impact of those drugs not only in increasing the growth of individuals living with achondroplasia but also in improving their quality of life.
The inflammatory CD40-CD40L pathway is implicated in various autoimmune diseases, but the activity status of this pathway in various stages of rheumatoid arthritis (RA) progression is unknown. In ...this study, we used gene signatures of CD40L stimulation derived from human immature dendritic cells and naive B cells to assess the expression of CD40-downstream genes in synovial tissues from anti-citrullinated protein Ab-positive arthralgia, undifferentiated arthritis (UA), early RA, and established RA cohorts in comparison with healthy donors. Interestingly, the expression of
and active full-length
was increased in the disease tissues, whereas that of a dominant-negative
isoform was decreased. Gene set variation analysis revealed that CD40L-responsive genes in immature dendritic cells and naive B cells were significantly enriched in synovial tissues from UA, early RA, and established RA patients. Additionally, CD40L-induced naive B cell genes were also significantly enriched in synovial tissues from arthralgia patients. In our efforts to characterize downstream mediators of CD40L signaling, we have identified
and
as novel components of the pathway. In conclusion, our data suggest that therapeutic CD40-CD40L blocking agents may prove efficacious not only in early and established RA, but also in inhibiting the progression of the disease from arthralgia or UA to RA.
Exosomes are cell-derived vesicles and are abundant in biological fluids; they contain RNA molecules which may serve as potential diagnostic biomarkers in 'precision medicine'. To promote the ...clinical application of exosomal RNA (exoRNA), many isolation methods must be compared and validated. Exosomes in cell culture medium (CCM) and serum may be isolated using ultracentrifugation (UC), ExoQuick or Total Exosome Isolation Reagent (TEI), and exoRNA may be extracted using TRIzol-LS, SeraMir, Total Exosome RNA Isolation (TER), HiPure Liquid RNA/miRNA kit (HLR), miRNeasy or exoRNeasy. ExoRNA was assessed using NanoDrop, Bioanalyzer 2100, quantitative polymerase chain reaction and high-throughput sequencing. UC showed the lowest recovery of particles, but the highest protein purity for exosome isolation. For isolation of exoRNA, we found that combinations of the TEI and TER methods resulted in high extraction efficiency and purity of small RNA obtained using CCM. High yield and a narrow size distribution pattern of small RNA were shown in exoRNA isolated by exoRNeasy from serum. In RNA profile analysis, the small RNA constituent ratio, miRNA content and amount varied as a result of methodological differences. This study showed that different methods may introduce variations in the concentration, purity and size of exosomes and exoRNA. Herein we discuss the advantages and disadvantages of each method and their application to different materials, therefore providing a reference according to research design.
Recurrent events, including cardiovascular events, are commonly observed in biomedical studies. Understanding the effects of various treatments on recurrent events and investigating the underlying ...mediation mechanisms by which treatments may reduce the frequency of recurrent events are crucial tasks for researchers. Although causal inference methods for recurrent event data have been proposed, they cannot be used to assess mediation. This study proposed a novel methodology of causal mediation analysis that accommodates recurrent outcomes of interest in a given individual. A formal definition of causal estimands (direct and indirect effects) within a counterfactual framework is given, and empirical expressions for these effects are identified. To estimate these effects, a semiparametric estimator with triple robustness against model misspecification was developed. The proposed methodology was demonstrated in a real‐world application. The method was applied to measure the effects of two diabetes drugs on the recurrence of cardiovascular disease and to examine the mediating role of kidney function in this process.
Camera calibration is a crucial prerequisite in many applications of computer vision. In this paper, a new geometry-based camera calibration technique is proposed, which resolves two main issues ...associated with the widely used Zhang's method: (i) the lack of guidelines to avoid outliers in the computation and (ii) the assumption of fixed camera focal length. The proposed approach is based on the closed-form solution of principal lines with their intersection being the principal point while each principal line can concisely represent relative orientation/position (up to one degree of freedom for both) between a special pair of coordinate systems of image plane and calibration pattern. With such analytically tractable image features, computations associated with the calibration are greatly simplified, while the guidelines in (i) can be established intuitively. Experimental results for synthetic and real data show that the proposed approach does compare favorably with Zhang's method, in terms of correctness, robustness, and flexibility, and addresses issues (i) and (ii) satisfactorily.
The development of novel polymerization capable of yielding polymers with low molecular weight distribution (Đ) is essential and significant in polymer chemistry, where monofunctional initiator ...contains only one initiation site in these polymerizations generally. Here, ketyl radical anion species is introduced to develop a novel Ketyl Mediated Polymerization (KMP), which enables radical polymerization at carbon radical site and anionic ring‐opening polymerization at oxygen anion site, respectively. Meanwhile, polymerization and corresponding organic synthesis generally couldn't be performed simultaneously in one pot. Through KMP, organic synthesis and polymerization are achieved in one pot, where small molecules (cyclopentane derivates) and polymers with low Đ are successfully prepared under mild condition simultaneously. At the initiation step, both organic synthesis and polymerization are initiated by single electron transfer reaction with ketyl radical anion formation. Cyclopentane derivates are synthesized through 3–3 coupling reaction and cyclization. Polystyrene and polycaprolactone with low Đ and a full monomer conversion are prepared by KMP via radical polymerization and anionic ring‐opening polymerization, respectively. This work therefore enables both organic synthesis and two different polymerizations from same initiation system, which saves time, labour, resource and energy and expands the reaction mode and method libraries of organic chemistry and polymer chemistry.
One ketyl radical anion can enable a 3–3 coupling reaction, radical polymerization at a carbon radical site, and anionic ring‐opening polymerization at an oxygen anion site. This results in simultaneous organic synthesis and polymerization in one pot; thereby cyclopentane derivates and polymers with low Đ are successfully prepared under mild conditions.
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