Light-Driven Metabolic Pathways in Non-Photosynthetic Biohybrid Bacteria.

Biomanufacturing via microorganisms relies on carbon substrates for molecular feedstocks and a source of energy to carry out enzymatic reactions. This creates metabolic bottlenecks and lowers the efficiency for substrate conversion. Nanoparticle biohybridization with proteins and whole cell surfaces can bypass the need for redox cofactor regeneration for improved secondary metabolite production in a non-specific manner. Here we propose using nanobiohybrid organisms (Nanorgs), intracellular protein-nanoparticle hybrids formed through the spontaneous coupling of core-shell quantum dots (QDs) with histidine-tagged enzymes in non-photosynthetic bacteria, for light-mediated control of bacterial metabolism. This proved to eliminate metabolic constrictions and replace glucose with light as the source of energy in Escherichia coli, with an increase in growth by 1.7-fold in 75 % reduced nutrient media. Metabolomic tracking through carbon isotope labeling confirmed flux shunting through targeted pathways, with accumulation of metabolites downstream of respective targets. Finally, application of Nanorgs with the Ehrlich pathway improved isobutanol titers/yield by 3.9-fold in 75 % less sugar from E. coli strains with no genetic alterations. These results demonstrate the promise of Nanorgs for metabolic engineering and low-cost biomanufacturing.

Diagnostic strategy of metagenomic next-generation sequencing for gram negative bacteria in respiratory infections.

OBJECTIVE: This study aims to identify the most effective diagnostic method for distinguishing pathogenic and non-pathogenic Gram-negative bacteria (GNB) in suspected pneumonia cases using metagenomic next-generation sequencing (mNGS) on bronchoalveolar lavage fluid (BALF) samples. METHODS: The effectiveness of mNGS was assessed on BALF samples collected from 583 patients, and the results were compared with those from microbiological culture and final clinical diagnosis. Three interpretational approaches were evaluated for diagnostic accuracy. RESULTS: mNGS outperformed culture significantly. Among the interpretational approaches, Clinical Interpretation (CI) demonstrated the best diagnostic performance with a sensitivity of 87.3%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 98.3%. CI's specificity was significantly higher than Simple Interpretation (SI) at 37.9%. Additionally, CI excluded some microorganisms identified as putative pathogens by SI, including Haemophilus parainfluenzae, Haemophilus parahaemolyticus, and Klebsiella aerogenes. CONCLUSION: Proper interpretation of mNGS data is crucial for accurately diagnosing respiratory infections caused by GNB. CI is recommended for this purpose.

Platelets as delivery vehicles for targeted enrichment of NO· to cerebral glioma for magnetic resonance imaging.

Using a magnetic resonance imaging (MRI) contrast agent, MRI has made substantial contributions to glioma diagnosis. Metal-free MRI agents, such as the nano free radical nitric oxide (NO·) micelle, can overcome the inherent toxicity of metal-based agents in certain patient populations. However, the low spatial resolution of nano NO· micelle in MRI limits its clinical development. In this study, we pretreated platelets (PLTs) and loaded them with nano NO· micelles to synthesize NO·@PLT, which can overcome the low contrast and poor in vivo stability of nitroxide-based MRI contrast agents. The PLTs can serve as potential drug carriers for targeting and delivering nano NO· micelles to gliomas and thus increase the contrast in T1-weighted imaging (T1WI) of MRI. This drug carrier system uses the unique tumor-targeting ability of PLTs and takes advantage of the high signal presentation of steady nano NO· micelles in T1WI, thereby ultimately achieving signal amplification of glioma in T1WI. With the effect of PLTs-tumor cell adhesion, NO·@PLT has per-nitroxide transverse relativities of approximately 2-fold greater than those of free NO· particles. These features allow a sufficient NO·@PLT concentration to accumulate in murine subcutaneous glioma tumors up from 5 min to 2.5 h (optimum at 1.5 h) after systemic administration. This results in MRI contrast comparable to that of metal-based agents. This study established a promising metal-free MRI contrast agent, NO·@PLT, for glioma diagnosis, because it has superior spatial resolution owing to its high glioma-targeting ability and has significant translational implications in the clinic.

Effectiveness of the Lilly Connected Care Program in Improving Glycemic Management Among Patients With Type 2 Diabetes in China: Retrospective Real-world Study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide public health concern. Mobile health management platforms could be a potential way to achieve effective glycemic control. OBJECTIVE: This study aimed to evaluate the real-world effectiveness of the Lilly Connected Care Program (LCCP) platform in glycemic control among patients with T2DM in China. METHODS: This retrospective study included Chinese patients with T2DM (aged ≥18 years) from April 1, 2017, to January 31, 2020, for the LCCP group and from January 1, 2015, to January 31, 2020, for the non-LCCP group. Propensity score matching was used to match the LCCP and non-LCCP groups to reduce confounding, with covariates including age, sex, the duration of diabetes, baseline hemoglobin A1c (HbA1c), and the number of oral antidiabetic medication classes. HbA1c reduction over 4 months, the proportions of patients achieving an HbA1c reduction of ≥0.5% or ≥1%, and the proportions of patients reaching to target HbA1c level of ≤6.5% or <7% were compared between the LCCP and non-LCCP groups. Multivariate linear regression was used to assess factors associated with HbA1c reduction. RESULTS: A total of 923 patients were included, among whom 303 pairs of patients were well matched after propensity score matching. HbA1c reduction during the 4-month follow-up was significantly larger in the LCCP group than the non-LCCP group (mean 2.21%, SD 2.37% vs mean 1.65%, SD 2.29%; P=.003). The LCCP group had a higher proportion of patients with an HbA1c reduction of ≥1% (209/303, 69% vs 174/303, 57.4%; P=.003) and ≥0.5% (229/303, 75.6% vs 206/303, 68%; P=.04). The proportions of patients reaching the target HbA1c level of ≤6.5% were significantly different between the LCCP and non-LCCP groups (88/303, 29% vs 61/303, 20.1%; P=.01), whereas the difference in the proportions of patients reaching the target HbA1c level of <7% was not statistically significant (LCCP vs non-LCCP: 128/303, 42.2% vs 109/303, 36%; P=.11). LCCP participation and higher baseline HbA1c were associated with a larger HbA1c reduction, whereas older age, longer diabetes duration, and higher baseline dose of premixed insulin analogue were associated with a smaller HbA1c reduction. CONCLUSIONS: The LCCP mobile platform was effective in glycemic control among patients with T2DM in China in the real world.

Nanorg Microbial Factories: Light-Driven Renewable Biochemical Synthesis Using Quantum Dot-Bacteria Nanobiohybrids.

Living cells do not interface naturally with nanoscale materials, although such artificial organisms can have unprecedented multifunctional properties, like wireless activation of enzyme function using electromagnetic stimuli. Realizing such interfacing in a nanobiohybrid organism (or nanorg) requires (1) chemical coupling via affinity binding and self-assembly, (2) the energetic coupling between optoelectronic states of artificial materials with the cellular process, and (3) the design of appropriate interfaces ensuring biocompatibility. Here we show that seven different core-shell quantum dots (QDs), with excitations ranging from ultraviolet to near-infrared energies, couple with targeted enzyme sites in bacteria. When illuminated by light, these QDs drive the renewable production of different biofuels and chemicals using carbon-dioxide (CO2), water, and nitrogen (from air) as substrates. These QDs use their zinc-rich shell facets for affinity attachment to the proteins. Cysteine zwitterion ligands enable uptake through the cell, facilitating cell survival. Together, these nanorgs catalyze light-induced air-water-CO2 reduction with a high turnover number (TON) of ∼106-108 (mols of product per mol of cells) to biofuels like isopropanol (IPA), 2,3-butanediol (BDO), C11-C15 methyl ketones (MKs), and hydrogen (H2); and chemicals such as formic acid (FA), ammonia (NH3), ethylene (C2H4), and degradable bioplastics polyhydroxybutyrate (PHB). Therefore, these resting cells function as nanomicrobial factories powered by light.

Titanium dioxide nanotube membranes for solar energy conversion: effect of deep and shallow dopants.

Nanostructured titanium dioxide (TiO2) has been intensively investigated as a material of choice for solar energy conversion in photocatalytic, photoelectrochemical, photovoltaic, and other photosensitized devices for converting light into chemical feedstocks or electricity. Towards management of light absorption in TiO2, while the nanotubular structure improves light absorption and simultaneous charge transfer to mitigate problems due to the indirect bandgap of the semiconductor, typically dopants are used to improve light absorption of incident solar irradiation in the wide bandgap of TiO2. While these dopants can be critical to the success of these solar energy conversion devices, their effect on photophysical and photoelectrochemical properties and detailed photokinetics are relatively under-studied. Here, we show the effect of deep and shallow metal dopants on the kinetics of photogenerated charged carriers in TiO2 and the resulting effect on photocatalytic and photoelectrochemical processes using these nanotube membranes. We performed a detailed optical, electronic, voltammetry and electrochemical impedance study to understand the effect of shallow and deep metal dopants (using undoped and niobium- and copper-doped TiO2 nanotubes) on light absorption, charge transport and charge transfer processes. Using wireless photocatalytic methylene blue degradation and carbon dioxide reduction, and wired photoelectrochemical device measurements, we elucidate the effect of different dopants on solar-to-fuel conversion efficiency and simultaneously describe the photokinetics using a model, to help design better energy conversion devices.

Transparent conducting oxide nanotubes.

Thin film or porous membranes made of hollow, transparent, conducting oxide (TCO) nanotubes, with high chemical stability, functionalized surfaces and large surface areas, can provide an excellent platform for a wide variety of nanostructured photovoltaic, photodetector, photoelectrochemical and photocatalytic devices. While large-bandgap oxide semiconductors offer transparency for incident light (below their nominal bandgap), their low carrier concentration and poor conductivity makes them unsuitable for charge conduction. Moreover, materials with high conductivity have nominally low bandgaps and hence poor light transmittance. Here, we demonstrate thin films and membranes made from TiO2 nanotubes heavily-doped with shallow Niobium (Nb) donors (up to 10%, without phase segregation), using a modified electrochemical anodization process, to fabricate transparent conducting hollow nanotubes. Temperature dependent current-voltage characteristics revealed that TiO2 TCO nanotubes, doped with 10% Nb, show metal-like behavior with resistivity decreasing from 6.5 × 10(-4) Ωcm at T = 300 K (compared to 6.5 × 10(-1) Ωcm for nominally undoped nanotubes) to 2.2 × 10(-4) Ωcm at T = 20 K. Optical properties, studied by reflectance measurements, showed light transmittance up to 90%, within wavelength range 400 nm-1000 nm. Nb doping also improves the field emission properties of TCO nanotubes demonstrating an order of magnitude increase in field-emitter current, compared to undoped samples.

No potential causal link between HP infection and IBD: A 2way Mendelian randomization study.

Recent epidemiological research suggests a possible negative correlation between Helicobacter pylori infection and inflammatory bowel disease (IBD). However, conflicting studies have provided unclear evidence regarding these causal relationships. Therefore, recommending specific prevention and treatment strategies for H. pylori infection and IBD is challenging. We used various antibodies (anti-H. pylori IgG, VacA, and GroEl) related to H. pylori infection as indicators. We acquired relevant genetic variants from public databases within the Genome-wide Association Studies (GWAS) dataset using IBDs tool variables from 2 different GWAS datasets. We thoroughly examined the data and screened for IVs that fulfilled these criteria. Subsequently, Bidirectional Mendelian randomization (MR) was conducted to predict the potential causality between the 2. To ensure the accuracy and robustness of our results, we conducted a series of sensitivity analyses. Based on our comprehensive MR analysis, no potential causal relationship was observed between H. pylori infection and IBD. Across various methodologies, including IVW, MR-Egger, and weighted median, our findings showed P values > .05. The only exception was observed in the reverse MR analysis using the MR-Egger method, which yielded a P value of < .05. However, because the IVW method is considered the most statistically significant method for MR, and its P value was > .05, we do not believe that a potential causal relationship exists between them. Our sensitivity analysis did not suggest significant horizontal pleiotropism. Although heterogeneity was detected in the analysis of IBD (IIBDGC source) versus H. pylori GroEL antibody levels (MR-Egger, Qp = 0.038; IVW, Qp = 0.043), the results remained reliable because we selected IVW as a random-effects model in our MR analysis method. Based on our MR research, no direct correlation was observed between H. pylori infection and IBD risk. This implies that eradicating H. pylori may not provide substantial benefits in preventing or treating regional IBD, and vice versa. Nevertheless, the use of H. pylori serological index substitution has limitations, and further research using histological diagnosis and additional MR studies is required to comprehensively assess the link between H. pylori infection and IBD.

Effect of smoking-related features and 731 immune cell phenotypes on esophageal cancer: a two-sample and mediated Mendelian randomized study.

Introduction: Numerous observational studies have indicated that smoking is a substantial risk factor for esophageal cancer. However, there is a shortage of research that delves into the specific causal relationship and potential mediators between the two. Our study aims to validate the correlation between smoking-related traits and esophageal cancer while exploring the possible mediating effects of immune factors. Methods: Initially, we conducted bidirectional univariate Mendelian Randomization (MR) analyses to forecast the causal effects linking smoking-related traits and esophageal cancer. Subsequently, we employed a two-step MR analysis to scrutinize immune cell phenotypes that could mediate these effects. Finally, the coefficient product method was employed to determine the precise mediating impact. Additionally, we have refined our sensitivity analysis to ensure the reliability of the outcomes. Results: After analysis, Smoking status: Never had a significant negative association with the incidence of esophageal cancer (inverse-variance weighted (IVW) method, p=1.82e-05, OR=0.10, 95%CI=0.04~0.29). Ever smoked (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) and Current tobacco smoking (IVW, p=1.49e-02, OR=4.31, 95%CI=1.33~13.94) showed the promoting effect on the pathogenesis of esophageal cancer. Through further examination, researchers discovered 21 immune cell phenotypes that have a causal relationship with esophageal cancer. After careful screening, two immune cell phenotypes were found to have potential mediating effects. In particular, it was observed that in the case of the preventive effect of Smoking status: Never on esophageal cancer, the absolute count of CD62L plasmacytoid dendritic cells mediated a reduction of 4.21%, while the mediating effect of CD27 in CD20-CD38-B cells was -4.12%. In addition, sensitivity analyses did not reveal significant heterogeneity or level pleiotropy. Conclusion: The study provides new evidence for the causal relationship between smoking-related features and esophageal cancer and proposes immune factors with potential mediating effects. However, this finding needs to be further demonstrated by more extensive clinical studies.

Embedded 3D printing of UV-curable thermosetting composites with continuous fiber.

Extrusion-based 3D printing methods with in-nozzle impregnation mechanisms have been extensively employed in the fabrication of continuous fiber composites. This study presents an innovative embedded 3D printing technique that addresses significant challenges associated with existing methods. The technique utilizes a deposition nozzle to precisely write continuous fibers below the resin. A laser beam is directed onto the resin surface, which simultaneously cures the resin around the fiber bundle. The printing method demonstrates its advantages in producing high-quality composite samples with well-aligned fibers, minimized void density, and outstanding mechanical properties. More importantly, it introduces several capabilities that are highly desirable in the fabrication of contemporary composites, but unattainable with existing methods, including the dynamic control of fiber volume fractions and the ability to change matrix materials during printing. Furthermore, it enables the printing of filaments along curved pathways and printing of overhanging filaments for hollow features without support materials. The developed printing method exhibits versatility in working with different commercially available feedstock resins and reinforcement fibers. It is anticipated to be an impactful approach for the future development of thermosetting composites with diverse structural or multifunctional applications.

Diagnostic Value of Dual-Energy CT Virtual Noncalcium for the Assessment of Bone Marrow Edema of Wrist in Patients with Rheumatoid Arthritis.

RATIONALE AND OBJECTIVES: To evaluate the value of dual-energy CT (DECT) virtual noncalcium (VNCa) images in the diagnosis of wrist bone marrow edema (BME) in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: 43 patients with wrist involvement in active RA prospectively underwent DECT and MRI. Functional DECT images reconstruction yielded VNCa images. MRI served as the reference standard for diagnosing BME. BME diagnosis differences between VNCa images and MRI were compared. Differences in CT values between BME and normal bone marrow were assessed. The optimal CT value for detecting BME in VNCa images was determined through ROC curve analysis. The correlation between VNCa images scores and RA disease activity was evaluated. RESULTS: There was a high agreement between VNCa images and MRI in diagnosing BME (Kappa=0.831). VNCa images showed a significant difference in CT values between BME and normal bone marrow (P < 0.001). A cut-off value of - 54.8 HU yielded a sensitivity, specificity, and accuracy of 90.72%, 94.30%, and 93.33%, respectively, for detecting BME on VNCa images. The area under the ROC curve was 0.937 for distinguishing BME from normal bone marrow. Conventional CT images showed no statistically significant difference (P = 0.174) in CT values between BME and normal bone marrow. The VNCa images BME scores were positively correlated with RA disease activity (r = 0.399). CONCLUSION: The DECT VNCa technique demonstrates its potential for diagnosing wrist BME in patients with RA and provides a valuable tool for assessing disease activity in RA. IMPORTANT FINDINGS: The DECT VNCa technique has the ability to distinguish between BME and normal bone marrow. The VNCa images BME scores were positively correlated with the disease activity in RA.

Solvent responsive magnetic dynamics of a dinuclear dysprosium single-molecule magnet.

A new dysprosium(III) phosphonate dimer {Dy(notpH4)(NO3)(H2O)}2·8H2O (1) [notpH6=1,4,7-triazacyclononane-1,4,7-triyl-tris(methylenephosphonic acid)] that contains two equivalent Dy(III) ions with a three-capped trigonal prism environment is reported. Complex 1 can be transformed into {Dy(notpH4)(NO3)(H2O)}2 (2) in a reversible manner by desorption and absorption of solvent water at ambient temperature. This process is accompanied by a large dielectric response. Magnetic studies reveal that both 1 and 2 show thermally activated magnetization relaxation as expected for single-molecule magnets. Moreover, the magnetic dynamics of the two compounds can be manipulated by controlling the number of solvent molecules at room temperature.

Utilizing Atmospheric Carbon Dioxide and Sunlight in Graphene Quantum Dot-Based Nano-Biohybrid Organisms for Making Carbon-Negative and Carbon-Neutral Products.

Increasing emissions of greenhouse gases compounded with legacy emissions in the earth's atmosphere poses an existential threat to human survival. One potential solution is creating carbon-negative and carbon-neutral materials, specifically for commodities used heavily throughout the globe, using a low-cost, scalable, and technologically and economically feasible process that can be deployed without the need for extensive infrastructure or skill requirements. Here, we demonstrate that nickel-functionalized graphene quantum dots (GQDs) can effectively couple to nonphotosynthetic bacteria at a cellular, molecular, and optoelectronic level, creating nanobiohybrid organisms (nanorgs) that enable the utilization of sunlight to convert carbon dioxide, air, and water into high-value-added chemicals such as ammonia (NH3), ethylene (C2H4), isopropanol (IPA), 2,3-butanediol (BDO), C11-C15 methyl ketones (MKs), and degradable bioplastics poly hydroxybutyrate (PHB) with high efficiency and selectivity. We demonstrate a high turnover number (TON) of up to 108 (mol of product per mol of cells), ease of application, facile scalability (demonstrated using a 30 L tank in a lab), and sustainable generation of carbon nanomaterials from recovered bacteria for creating nanorgs without the use of any toxic chemicals or materials. These findings can have important implications for the further development of sustainable processes for making carbon-negative materials using nanorgs.

Salinity-dependent changes in branchial morphometry and Na+ , K+ -ATPase responses of euryhaline Asian sea bass, Lates calcarifer.

Asian sea bass (Lates calcarifer Bloch, 1790) is a euryhaline fish widely cultured in Asia and Australia. Although it is common to culture Asian sea bass at different salinities, osmoregulatory responses of Asian sea bass during acclimation to various salinities have not been fully observed. In this study, we used scanning electron microscopy to observe the morphology of the ionocyte apical membrane of Asian sea bass acclimated to fresh water (FW), 10‰ brackish water (BW10), 20‰ brackish water (BW20), and seawater (SW; 35‰). Three types of ionocytes were identified in FW and BW fish: (I) flat type with microvilli, (II) basin type with microvilli, and (III) small- hole type. Flat type I ionocytes were also observed in the lamellae of the FW fish. In contrast, two types of ionocytes were identified in SW fish: (III) small-hole type and (IV) big-hole type. Furthermore, we observed Na+ , K+ -ATPase (NKA) immunoreactive cells in the gills, which represent the localization of ionocytes. The highest protein abundance was observed in the SW and FW groups, whereas the highest activity was observed in the SW group. In contrast, the BW10 group had the lowest protein abundance and activity. This study demonstrates the effects of osmoregulatory responses on the morphology and density of ionocytes, as well as protein abundance and activity of NKA. In this study, we found that Asian sea bass had the lowest osmoregulatory response in BW10, because the lowest amounts of ionocytes and NKA were required to maintain osmolality at this salinity.

Light-driven Transformation of Carbon Monoxide into Hydrocarbons using CdS@ZnS : VFe Protein Biohybrids.

Enzymatic Fisher-Tropsch (FT) process catalyzed by vanadium (V)-nitrogenase can convert carbon monoxide (CO) to longer-chain hydrocarbons (>C2) under ambient conditions, although this process requires high-cost reducing agent(s) and/or the ATP-dependent reductase as electron and energy sources. Using visible light-activated CdS@ZnS (CZS) core-shell quantum dots (QDs) as alternative reducing equivalent for the catalytic component (VFe protein) of V-nitrogenase, we first report a CZS : VFe biohybrid system that enables effective photo-enzymatic C-C coupling reactions, hydrogenating CO into hydrocarbon fuels (up to C4) that can be hardly achieved with conventional inorganic photocatalysts. Surface ligand engineering optimizes molecular and opto-electronic coupling between QDs and the VFe protein, realizing high efficiency (internal quantum yield >56 %), ATP-independent, photon-to-fuel production, achieving an electron turnover number of >900, that is 72 % compared to the natural ATP-coupled transformation of CO into hydrocarbons by V-nitrogenase. The selectivity of products can be controlled by irradiation conditions, with higher photon flux favoring (longer-chain) hydrocarbon generation. The CZS : VFe biohybrids not only can find applications in industrial CO removal for high-value-added chemical production by using the cheap, renewable solar energy, but also will inspire related research interests in understanding the molecular and electronic processes in photo-biocatalytic systems.

3D Printing of continuous fiber composites using two-stage UV curable resin.

3D printing allows for moldless fabrication of continuous fiber composites with high design freedom and low manufacturing cost per part, which makes it particularly well-suited for rapid prototyping and composite product development. Compared to thermal-curable resins, UV-curable resins enable the 3D printing of composites with high fiber content and faster manufacturing speeds. However, the printed composites exhibit low mechanical strength and weak interfacial bonding for high-performance engineering applications. In addition, they are typically not reprocessable or repairable; if they could be, it would dramatically benefit the rapid prototyping of composite products with improved durability, reliability, cost savings, and streamlined workflow. In this study, we demonstrate that the recently emerged two-stage UV-curable resin is an ideal material candidate to tackle these grand challenges in 3D printing of thermoset composites with continuous carbon fiber. The resin consists primarily of acrylate monomers and crosslinkers with exchangeable covalent bonds. During the printing process, composite filaments containing up to 30.9% carbon fiber can be rapidly deposited and solidified through UV irradiation. After printing, the printed composites are subjected to post-heating. Their mechanical stiffness, strength, and inter-filament bonding are significantly enhanced due to the bond exchange reactions within the thermoset matrix. Furthermore, the utilization of the two-stage curable resin enables the repair, reshaping, and recycling of 3D printed thermosetting composites. This study represents the first detailed study to explore the benefits of using two-stage UV curable resins for composite printing. The fundamental understanding could potentially be extended to other types of two-stage curable resins with different molecular mechanisms.

Study Design and Baseline Characteristics of Patients with T2DM in the Post-marketing Safety Study of Dulaglutide in China (TRUST-CHN).

BACKGROUND: TRUST-CHN is a prospective, post-marketing safety study in patients with type 2 diabetes mellitus (T2DM) in China to evaluate the safety and effectiveness of dulaglutide in real-world clinical practice. We report here the study design and baseline characteristics of enrolled patients. METHODS: The study design was described, and baseline data were analyzed, including demographic characteristics, T2DM duration, comorbidities, dulaglutide treatment patterns, and concomitant medications. RESULTS: For the present analysis of this ongoing study, data were collected from January 2020 to November 2021. A total of 3313 patients were enrolled, of whom 3294 patients were included in the safety analysis. In total, 1047 patients had a prior history of dulaglutide use before being enrolled in the study. The mean (standard deviation [SD]) age of study subjects was 50.1 (13.2) years, 85.1% were aged < 65 years; 67.9% were male, and 35.9% had an education of university level or higher. Mean (SD) duration of T2DM was 6.4 (6.7) years. Baseline mean (SD) glycated hemoglobin was 8.8% (2.2%), and mean (SD) body mass index was 28.1 (4.1) kg/m2. A total of 2867 (87%) patients had at least one comorbidity, the most frequently reported of which were overweight/obesity (87.1%), hyperlipidemia (50.5%), hypertension (47.9%), diabetic neuropathy (18.9%), and coronary artery disease (15.7%). Almost all (99.7%) patients were treated with 1.5 mg dulaglutide; at baseline, 24.8% were treated with this medication as monotherapy and 75.2% in combination therapy with other medications, including metformin (42.3%), sodium glucose co-transporter2 inhibitor (26.7%), insulin (18.3%), α-glucosidase inhibitor (13.1%), sulfonylurea (5.3%), dipeptidyl peptidase 4 inhibitor (4.4%), glucagon-like peptide 1 receptor agonist (2.7%), and thiazolidinedione (2.4%). CONCLUSION: The present analysis revealed real-world baseline characteristics of patients with T2DM in China who use dulaglutide enrolled in TRUST-CHN. These data will enable further exploration of the characteristics of patients with T2DM in China and provide an insight on the current use of dulaglutide in clinical practice.

Nanoligomers Targeting Human miRNA for the Treatment of Severe COVID-19 Are Safe and Nontoxic in Mice.

The devastating effects of the coronavirus disease 2019 (COVID-19) pandemic have made clear a global necessity for antiviral strategies. Most fatalities associated with infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result at least partially from uncontrolled host immune response. Here, we use an antisense compound targeting a previously identified microRNA (miRNA) linked to severe cases of COVID-19. The compound binds specifically to the miRNA in question, miR-2392, which is produced by human cells in several disease states. The safety and biodistribution of this compound were tested in a mouse model via intranasal, intraperitoneal, and intravenous administration. The compound did not cause any toxic responses in mice based on measured parameters, including body weight, serum biomarkers for inflammation, and organ histopathology. No immunogenicity from the compound was observed with any administration route. Intranasal administration resulted in excellent and rapid biodistribution to the lungs, the main site of infection for SARS-CoV-2. Pharmacokinetic and biodistribution studies reveal delivery to different organs, including lungs, liver, kidneys, and spleen. The compound was largely cleared through the kidneys and excreted via the urine, with no accumulation observed in first-pass organs. The compound is concluded to be a safe potential antiviral treatment for COVID-19.

Direct medical costs of obesity in the United States and the most populous states.

BACKGROUND: After a dramatic increase in prevalence over several decades, obesity has become a major public health crisis in the United States. Research to date has consistently demonstrated a correlation between obesity and higher medical costs for a variety of U.S. subpopulations and specific categories of care. However, by examining associations rather than causal effects, previous studies likely underestimated the effect of obesity on medical expenditures. OBJECTIVE: To estimate the causal effect of obesity on direct medical care costs at the national and state levels. METHODS: This study is a pooled cross-sectional analysis of retrospective data from the 2001-2016 Medical Expenditure Panel Surveys. Adults aged 20-65 years with a biological child living in the household were included in the study sample. Primary outcomes were individual-level medical expenditures due to obesity, overall, as well as separately by type of payer and category of medical care. Results were reported at the national level and separately for the 20 most populous states. The expenditure estimates were obtained from 2-part models of instrumental variables in which the respondent's body mass index (BMI) was instrumented using the BMI of their biological child. RESULTS: Adults with obesity in the United States compared with those with normal weight experienced higher annual medical care costs by $2,505 or 100%, with costs increasing significantly with class of obesity, from 68.4% for class 1 to 233.6% for class 3. The effects of obesity raised costs in every category of care: inpatient, outpatient, and prescription drugs. Increases in medical expenditures due to obesity were higher for adults covered by public health insurance programs ($2,868) than for those having private health insurance ($2,058). In 2016, the aggregate medical cost due to obesity among adults in the United States was $260.6 billion. The increase in individual-level expenditures due to obesity varied considerably by state (e.g., 24.0% in Florida, 66.4% in New York, and 104.9% in Texas). CONCLUSIONS: The 2-part models of instrumental variables, which estimate the causal effects of obesity on direct medical costs, showed that the effect of obesity is greater than suggested by previous studies, which estimated only correlations. Much of the aggregate national cost of obesity-$260.6 billion-represents external costs, providing a rationale for interventions to prevent and reduce obesity. DISCLOSURES: Novo Nordisk financed the development of the study design, analysis, and interpretation of data, as well as writing support of the manuscript. Cawley, Biener, and Meyerhoefer received financial support from Novo Nordisk to conduct the research study on which this manuscript is based. Smolarz and Ramasamy are employees of Novo Nordisk. Ding and Zvenyach have no conflicts to declare. Our research has been presented as a poster at the 2020 Academy Health Annual Research Meeting (Virtual), July 28-August 6, 2020.

Job Absenteeism Costs of Obesity in the United States: National and State-Level Estimates.

OBJECTIVE: To estimate the causal effect of obesity on job absenteeism and the associated lost productivity in the United States, both nationwide and by state. METHODS: We conducted a retrospective pooled cross-sectional analysis using the 2001 to 2016 Medical Expenditure Panel Survey and estimated two-part models of instrumental variables. RESULTS: Obesity, relative to normal weight, raises job absenteeism due to injury or illness by 3.0 days per year (128%). Annual productivity loss due to obesity ranges from $271 to $542 (lower/upper bound) per employee with obesity, with national productivity losses ranging from $13.4 to $26.8 billion in 2016. Trends in state-level estimates mirror those at the national level, varying across states. CONCLUSIONS: Obesity significantly raises job absenteeism. Reductions in job absenteeism should be included when calculating the cost-effectiveness of interventions to prevent or reduce obesity among employed adults.