Efficient integration of aggregate data and individual participant data in one-way mixed models.

Often both aggregate data (AD) studies and individual participant data (IPD) studies are available for specific treatments. Combining these two sources of data could improve the overall meta-analytic estimates of treatment effects. Moreover, often for some studies with AD, the associated IPD maybe available, albeit at some extra effort or cost to the analyst. We propose a method for combining treatment effects across trials when the response is from the exponential family of distribution and hence a generalized linear model structure can be used. We consider the case when treatment effects are fixed and common across studies. Using the proposed combination method, we study the relative efficiency of analyzing all IPD studies vs combining various percentages of AD and IPD studies. For many different models, design constraints under which the AD estimators are the IPD estimators, and hence fully efficient, are known. For such models, we advocate a selection procedure that chooses AD studies over IPD studies in a manner that force least departure from design constraints and hence ensures an efficient combined AD and IPD estimator.

Empirical Treatment With Carbapenem vs Third-generation Cephalosporin for Treatment of Spontaneous Bacterial Peritonitis.

BACKGROUND & AIMS: Third-generation cephalosporins (TGCs) are recommended as first-line antibiotics for treatment of spontaneous bacterial peritonitis (SBP). However, antibiotics against multidrug-resistant organisms (such as carbapenems) might be necessary. We aimed to evaluate whether carbapenems are superior to TGC for treatment of SBP. METHODS: We performed a retrospective study of 865 consecutive patients with a first presentation of SBP (275 culture positive; 103 with TGC-resistant bacterial infections) treated at 7 referral centers in Korea, from September 2013 through January 2018. The primary outcome was in-hospital mortality. We made all comparisons using data from patients whose baseline characteristics were balanced by inverse probability of treatment weighting. RESULTS: Of patients who initially received empirical treatment with antibiotics, 95 (11.0%) received carbapenems and 655 (75.7%) received TGCs. Among the entire study cohort, there was no significant difference in in-hospital mortality between the carbapenem (25.8%) and TGC (25.3%) groups (adjusted odds ratio [aOR], 0.97; 95% CI, 0.85-1.11; P = .66). In the subgroup of patients with high chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores (score of 7 or greater, n = 314), carbapenem treatment was associated with lower in-hospital mortality (23.1%) than in the TGC group (38.8%) (aOR, 0.84; 95% CI, 0.75-0.94; P=.002). In contrast, among patients with lower CLIF-SOFA scores (n = 436), in-hospital mortality did not differ significantly between the carbapenem group (24.7%) and the TGC group (16.0%) (aOR, 1.06; 95% CI, 0.85-1.32; P = .58). CONCLUSIONS: For patients with a first presentation of SBP, empirical treatment with carbapenem does not reduce in-hospital mortality compared to treatment with TGCs. However, among critically ill patients (CLIF-SOFA scores ≥7), empirical carbapenem treatment was significantly associated with lower in-hospital mortality than TGCs.

Adaptive local false discovery rate procedures for highly spiky data and their application RNA sequencing data of yeast SET4 deletion mutants.

Chromatin dynamics are central to the regulation of gene expression and genome stability. In order to improve understanding of the factors regulating chromatin dynamics, the genes encoding these factors are deleted and the differential gene expression profiles are determined using approaches such as RNA sequencing. Here, we analyzed a gene expression dataset aimed at uncovering the function of the relatively uncharacterized chromatin regulator, Set4, in the model system Saccharomyces cerevisiae (budding yeast). The main theme of this paper focuses on identifying the highly differentially expressed genes in cells deleted for Set4 (referred to as Set4 Δ mutant dataset) compared to the wild-type yeast cells. The Set4 Δ mutant data produce a spiky distribution on the log-fold changes of their expressions, and it is reasonably assumed that genes which are not highly differentially expressed come from a mixture of two normal distributions. We propose an adaptive local false discovery rate (FDR) procedure, which estimates the null distribution of the log-fold changes empirically. We numerically show that, unlike existing approaches, our proposed method controls FDR at the aimed level (0.05) and also has competitive power in finding differentially expressed genes. Finally, we apply our procedure to analyzing the Set4 Δ mutant dataset.

Two-Dimensional WO3 Nanosheets Chemically Converted from Layered WS2 for High-Performance Electrochromic Devices.

Two-dimensional (2D) transitional metal oxides (TMOs) are an attractive class of materials due to the combined advantages of high active surface area, enhanced electrochemical properties, and stability. Among the 2D TMOs, 2D tungsten oxide (WO3) nanosheets possess great potential in electrochemical applications, particularly in electrochromic (EC) devices. However, feasible production of 2D WO3 nanosheets is challenging due to the innate 3D crystallographic structure of WO3. Here we report a novel solution-phase synthesis of 2D WO3 nanosheets through simple oxidation from 2D tungsten disulfide (WS2) nanosheets exfoliated from bulk WS2 powder. The complete conversion from WS2 into WO3 was confirmed through crystallographic and elemental analyses, followed by validation of the 2D WO3 nanosheets applied in the EC device. The EC device showed color modulation of 62.57% at 700 nm wavelength, which is 3.43 times higher than the value of the conventional device using bulk WO3 powder, while also showing enhancement of ∼46.62% and ∼62.71% in switching response-time (coloration and bleaching). The mechanism of enhancement was rationalized through comparative analysis based on the thickness of the WO3 components. In the future, 2D WO3 nanosheets could also be used for other promising applications such as sensors, catalysis, thermoelectric, and energy conversion.

Multifunctional Hierarchically-Assembled Hydrogel Particles with Pollen Grains via Pickering Suspension Polymerization.

Hierarchical assembly of heterogeneous particles is of great importance to interface and colloid science. In this work, a facile but powerful approach for the large-scale production of multifunctional hydrogel particles armored with biological colloidal species is developed by combining Pickering stabilization and photopolymerization. Biocompatible hollow pollen grains extracted from naturally occurring pollen species with an average diameter of ∼32 µm serve as universal solid emulsifiers dispersed in an oil phase and are self-assembled at the interface between an oil phase and a photo-cross-linkable hydrogel to make water-in-oil (W/O) emulsion droplets. While droplets are solidified into hydrogel particles by UV-induced free-radical polymerization, self-assembled hollow pollen grains are transformed to a robust shell on hydrogel particles with supracolloidal structures. The physically adsorbed hollow pollen grains on the hydrogel core can be released by a hydration-induced swelling of hollow pollen grains, leading to a transient floating behavior of core-shell particles. The size of the resultant core-shell particles is easily controlled by tailoring the process parameters such as a liquid volume or a loading mass of hollow pollen grains. The incorporation of magnetic or upconverting luminescent nanoparticles into a hydrogel core successfully expands the functionality of core-shell particles that can provide new design opportunities for floating drug delivery or ecofriendly proppants.

Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples.

The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate somatic mutations found in one or few individuals with functional roles have been largely unsuccessful. Traditional methods for identifying somatic variants that drive cancer are 'gene-centric' in that they consider only somatic variants within a particular gene and make no comparison to other similar genes in the same family that may play a similar role in cancer. In this work, we present oncodomain hotspots, a new 'domain-centric' method for identifying clusters of somatic mutations across entire gene families using protein domain models. Our analysis confirms that our approach creates a framework for leveraging structural and functional information encapsulated by protein domains into the analysis of somatic variants in cancer, enabling the assessment of even rare somatic variants by comparison to similar genes. Our results reveal a vast landscape of somatic variants that act at the level of domain families altering pathways known to be involved with cancer such as protein phosphorylation, signaling, gene regulation, and cell metabolism. Due to oncodomain hotspots' unique ability to assess rare variants, we expect our method to become an important tool for the analysis of sequenced tumor genomes, complementing existing methods.

Empirical null estimation using zero-inflated discrete mixture distributions and its application to protein domain data.

In recent mutation studies, analyses based on protein domain positions are gaining popularity over gene-centric approaches since the latter have limitations in considering the functional context that the position of the mutation provides. This presents a large-scale simultaneous inference problem, with hundreds of hypothesis tests to consider at the same time. This article aims to select significant mutation counts while controlling a given level of Type I error via False Discovery Rate (FDR) procedures. One main assumption is that the mutation counts follow a zero-inflated model in order to account for the true zeros in the count model and the excess zeros. The class of models considered is the Zero-inflated Generalized Poisson (ZIGP) distribution. Furthermore, we assumed that there exists a cut-off value such that smaller counts than this value are generated from the null distribution. We present several data-dependent methods to determine the cut-off value. We also consider a two-stage procedure based on screening process so that the number of mutations exceeding a certain value should be considered as significant mutations. Simulated and protein domain data sets are used to illustrate this procedure in estimation of the empirical null using a mixture of discrete distributions. Overall, while maintaining control of the FDR, the proposed two-stage testing procedure has superior empirical power.

Chemometric Methods to Quantify 1D and 2D NMR Spectral Differences Among Similar Protein Therapeutics.

NMR spectroscopy is an emerging analytical tool for measuring complex drug product qualities, e.g., protein higher order structure (HOS) or heparin chemical composition. Most drug NMR spectra have been visually analyzed; however, NMR spectra are inherently quantitative and multivariate and thus suitable for chemometric analysis. Therefore, quantitative measurements derived from chemometric comparisons between spectra could be a key step in establishing acceptance criteria for a new generic drug or a new batch after manufacture change. To measure the capability of chemometric methods to differentiate comparator NMR spectra, we calculated inter-spectra difference metrics on 1D/2D spectra of two insulin drugs, Humulin R® and Novolin R®, from different manufacturers. Both insulin drugs have an identical drug substance but differ in formulation. Chemometric methods (i.e., principal component analysis (PCA), 3-way Tucker3 or graph invariant (GI)) were performed to calculate Mahalanobis distance (D M) between the two brands (inter-brand) and distance ratio (D R) among the different lots (intra-brand). The PCA on 1D inter-brand spectral comparison yielded a D M value of 213. In comparing 2D spectra, the Tucker3 analysis yielded the highest differentiability value (D M = 305) in the comparisons made followed by PCA (D M = 255) then the GI method (D M = 40). In conclusion, drug quality comparisons among different lots might benefit from PCA on 1D spectra for rapidly comparing many samples, while higher resolution but more time-consuming 2D-NMR-data-based comparisons using Tucker3 analysis or PCA provide a greater level of assurance for drug structural similarity evaluation between drug brands.

CARDIAC MAGNETIC RESONANCE IMAGING OF PATENT DUCTUS ARTERIOSUS IN THREE DOGS.

Patent ductus arteriosus (PDA) is the most common congenital cardiovascular disorder in dogs and requires an accurate diagnosis for an appropriate treatment. Cardiac MRI (cMRI) has been reported as a method for characterization of canine thoracic vasculature. However, to the authors' knowledge, no published studies describe evaluation of canine PDA through cMRI. Three dogs were selected for this exploratory study. Electrocardiogram gating and breath-hold techniques were performed using a 3T MR scanner. Both black blood imaging and bright blood cine acquisitions were performed. Quantification of stroke volume (SV) and shunting volume were calculated using a stack of short-axis cine images. Additional 4D (three-spatial dimensions plus time)-TRAK (time-resolved MR angiography with keyhole) sequences were conducted in patient 2 to verify other vasculature abnormality. Black blood images clearly depicted the course of the ductus from the descending aorta to the pulmonary artery in all three dogs. Morphological evaluation of PDA classified patients 1 and 2 as Type 2a and patient 3 as Type 1. Patient 2 was confirmed to have a concurrent persistent left cranial vena cava. Left ventricular SV, right ventricular SV, and left-to-right SV ratio were 12.4 ml, 3.36 ml, and 3.704, respectively, in patient 1; 6.85 ml, 1.22 ml, and 5.60 in the patient 2; and 3.67 ml, 2.14 ml, and 1.702 in patient 3. Findings indicated that cMRI is a feasible method for characterizing the morphology of PDA and extracardiac vasculature anomalies in dogs.

Plug-in tests for nonequivalence of means of independent normal populations.

In this paper, we consider the problem of testing nonequivalence of several independent normal population means. It is a well-known problem to test the equality of several means using the analysis of variance (ANOVA). Instead of determining the equality, one may consider more flexible homogeneity, which allows a predetermined level of difference. This problem is known as testing nonequivalence of populations. We propose the plug-in statistics for two different measures of variability: the sum of the absolute deviations and the maximum of the absolute deviations. For each test, the least favorable configuration (LFC) to ensure the maximum rejection probability under the null hypothesis is investigated. Furthermore, we demonstrate the numerical studies based on both simulation and real data to evaluate the plug-in tests and compare these with the range test.

Medical treatment of osteoarthritis: botanical pharmacologic aspect.

Osteoarthritis (OA) is the most common form of arthritis, and its prevalence is expected to further increase as our society ages. Despite many approaches to cure OA, no drugs are currently proven to modulate the progression of OA. Nowadays, new OA treatment options are holistically developed and one of the approaches of treatment option is botanical drugs. Some botanical drugs for OA have shown both therapeutic effect comparable to refined drugs in small studies and fewer side effects. Hence, there are various health functional foods which are known to relieve symptoms of OA. However, since there are many botanical products, clinicians are not familiar to the efficacy of each botanical product, making it challenging to use them appropriately in clinical practice. Here, we summarize the botanical products available for treating OA, including prescription botanical drugs and health functional foods available in Korea. Further studies and the purification of effective molecules from botanical products will be necessary in future.

Soft elastomeric nanopillar stamps for enhancing absorption in organic thin-film solar cells.

An elastomeric poly(dimethylsiloxane) (PDMS) block engraved with periodically arrayed nanopillars serves as a transferable light-trapping stamp for encapsulated organic thin-film solar cells. Diffracted light rays from the stamp interfere with one another and self-focus onto the active layer of the solar cell, generating enhanced absorption, as indicated in the current density-voltage measurements.

Through-hole composite membrane with an ultrathin oxide shell for highly robust and transparent air filters.

Exploring pore structures that are optically transparent and have high filtration efficiency for ultrafine dust is very important for realizing passive window filters for indoor air purification. Herein, a polyester track-etched (PETE) membrane with vertically perforated micropores is investigated as a cost-effective candidate for transparent window filters. The pore size, which governs transparency and filtration efficiency, can be precisely tuned by conformally depositing an ultrathin oxide layer on the PETE membrane via atomic layer deposition. The maximum visible light transmittance (∼81.2 %) was achieved with an alumina layer of approximately 55 nm, and the resulting composite membrane exhibited competitive filtration efficiency compared to commercial products. The chemically inert alumina layer also increased resistance to various external stimuli and enabled simple cleaning of the contaminated membrane surface with a solvent. The membrane installed on an insect screen effectively maintained its filtration performance (∼85 % for PM2.5) even after 10 reuse cycles under extremely harsh conditions (PM2.5 concentration: ∼5000 µg cm-3). The proposed through-hole composite membrane can expand the choice of aesthetic window filters to situations that require high outside visibility and daylighting.

A review of osteoarthritis signaling intervention using small-molecule inhibitors.

Numerous small-molecule inhibitors (SMIs) have been approved as adjuvant or first-line therapies for malignancies. Based on cancer treatment using SMIs, next-generation SMIs that can be used to optimize the therapeutic index, overcome drug resistance, and establish combination therapies are in development. Osteoarthritis (OA) is the most common chronic joint disease with senescence, and there are various approaches to OA treatment; however, the gold standard treatment is controversial. Therefore, in this manuscript, we demonstrated the potential of using SMIs in OA treatment and described the general strategies for using SMIs in OA treatment.

Revisit to functional data analysis of sleeping energy expenditure.

In this paper, we consider the classification problem of functional data including the sleeping energy expenditure (SEE) data, focusing on functional classification. Many existing classification rules are not effective in distinguishing the two classes of SEE data, because the trajectories of each observation have very different patterns for each class. It is often observed that some aspect of data such as the variability of paths is helpful in classification of functional data. To reflect this issue, we introduce a variable measuring the length of path in functional data and then propose a logistic model with fused lasso that considers the behavior of fluctuation of path as well as local correlations within each path. Our proposed model shows a significant improvement over some models used in the existing literature on the classification accuracy rate of functional data such as SEE data. We carry out simulation studies to show the finite sample performance and the gain that it makes in comparison with fused lasso without considering path length. With two more real datasets studied in some existing literature, we demonstrate that the new model achieves better or similar accuracy rate than the best accuracy rates reported in those studies.

Effect of C-terminus Conjugation via Different Conjugation Chemistries on In Vivo Activity of Albumin-Conjugated Recombinant GLP-1.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone with tremendous therapeutic potential for treating type 2 diabetes mellitus. However, the short half-life of its native form is a significant drawback. We previously prolonged the plasma half-life of GLP-1 via site-specific conjugation of human serum albumin (HSA) at position 16 of recombinant GLP-1 using site-specific incorporation of p-azido-phenylalanine (AzF) and strain-promoted azide-alkyne cycloaddition (SPAAC). However, the resulting conjugate GLP1_8G16AzF-HSA showed only moderate in vivo glucose-lowering activity, probably due to perturbed interactions with GLP-1 receptor (GLP-1R) caused by the albumin-linker. To identify albumin-conjugated GLP-1 variants with enhanced in vivo glucose-lowering activity, we investigated the conjugation of HSA to a C-terminal region of GLP-1 to reduce steric hindrance by the albumin-linker using two different conjugation chemistries. GLP-1 variants GLP1_8G37AzF-HSA and GLP1_8G37C-HSA were prepared using SPAAC and Michael addition, respectively. GLP1_8G37C-HSA exhibited a higher glucose-lowering activity in vivo than GLP1_8G16AzF-HSA, while GLP1_8G37AzF-HSA did not. Another GLP-1 variant, GLP1_8A37C-HSA, had a glycine to alanine mutation at position 8 and albumin at its C-terminus and exhibited in vivo glucose-lowering activity comparable to that of GLP1_8G37C-HSA, despite a moderately shorter plasma half-life. These results showed that site-specific HSA conjugation to the C-terminus of GLP-1 via Michael addition could be used to generate GLP-1 variants with enhanced glucose-lowering activity and prolonged plasma half-life in vivo.

Proximity field nanopatterning of azopolymer thin films.

A method for inscribing surface relief gratings in azopolymer thin films via proximity field nanopatterning is reported. Azopolymers prepared by ring opening metathesis polymerization were cast as thin films and brought into conformal contact with transparent polydimethylsiloxane phase masks. Irradiation of the film surface through the phase masks induces mass transport of azopolymer that generates surface relief structures on the basis of the intensity modulation of the light by structures on the phase mask. The experimental images obtained matched well with those produced by optical simulation. A wide variety of structures could be inscribed in the film surface which depended on the molecular weight of the azopolymer and irradiation time. Control experiments conducted suggest that the process is entirely photonic and that the presence of the phase mask on the film surface did not affect the inscription process.

Association between hemoglobin variability and incidence of hypertension over 40 years: a Korean national cohort study.

Hemoglobin level determines blood viscosity and as hemoglobin level rises, blood pressure rises. However, hemoglobin level in individuals is not fixed and change in hemoglobin is affected by various clinical conditions. The purpose of this study is to investigate whether the hemoglobin variability affects the development of hypertension using Korean cohort database. This study was conducted with 94,798 adults (age ≥ 40 years) who visited the health screening in 2006 or 2007 (index year) and had at least 3 health screenings from 2002 to 2007. Hemoglobin variability was assessed by 3 indices of coefficient of variation (CV), standard deviation, and variability independent of the mean. Cox proportional hazard regression analysis was performed for each index of quartile groups (Q1-Q4). A total of 29,145 participants (30.7%) had the incidence of hypertension during a median follow-up of 7.4 ± 2.5 years. In the multivariable adjusted model, the hazard ratio and 95% confidence interval for incidence of hypertension of Q2, Q3, and Q4 compared with Q1 of hemoglobin variability CV were 1.014 [0.981-1.047], 1.064 [1.030-1.099] and 1.094 [1.059-1.131] respectively. The results were consistent in various sensitivity and subgroup analyses. This study showed that hemoglobin variability could be associated with hypertension development.

The Minimal Effect of Linker Length for Fatty Acid Conjugation to a Small Protein on the Serum Half-Life Extension.

Conjugation of serum albumin or one of its ligands (such as fatty acid) has been an effective strategy to prolong the serum half-lives of drugs via neonatal Fc receptor (FcRn)-mediated recycling of albumin. So far, fatty acid (FA) has been effective in prolonging the serum half-lives for therapeutic peptides and small proteins, but not for large therapeutic proteins. Very recently, it was reported a large protein conjugated to FA competes with the binding of FcRn with serum albumin, leading to limited serum half-life extension, because primary FA binding sites in serum albumin partially overlap with FcRn binding sites. In order to prevent such competition, longer linkers between FA and the large proteins were required. Herein, we hypothesized that small proteins do not cause substantial competition for FcRn binding to albumin, resulting in the extended serum half-life. Using a small protein (28 kDa), we investigated whether the intramolecular distance in FA-protein conjugate affects the FcRn binding with albumin and serum half-life using linkers with varying lengths. Unlike with the FA-conjugated large protein, all FA-conjugated small proteins with different linkers exhibited comparable the FcRn binding to albumin and extended serum half-life.

Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide.

The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A "clickable" non-natural amino acid-p-azido-l-phenylalanine (AzF)-was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide-alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives.