Molecular estimation of alteration in intestinal microbial composition in Hashimoto's thyroiditis patients

The gut microbiota has a crucial effect on human health and physiology. Hypothyroid Hashimoto’s thyroiditis (HT) is an autoimmune disorder manifested with environmental and genetic factors. However, it is hypothesized that intestinal microbes might play a vital role in the pathogenesis of HT. The aim of current was to investigate and characterize the gut microbial composition of HT patients both quantitatively and qualitatively. The fecal samples from 29 HT patients and 12 healthy individuals were collected. The PCR-DGGE targeted V3 site of 16S rRNA gene and real time PCR for Bifidobacterium Lactobacillus, Bacteroides vulgatus and Clostridium leptum were performed. Pyrosequencing of 16S rRNA gene with V4 location was performed on 20 randomly selected samples. The comparative analysis of diversity and richness indices revealed diversification of gut microbiota in HT as compared to control. The statistical data elucidate the alterations in phyla of HT patients which was also affirmed at the family level. We observed the declined abundance of Prevotella_9 and Dialister, while elevated genera of the diseased group included Escherichia-Shigella and Parasutterella. The alteration in gut microbial configuration was also monitored at the species level, which showed an increased abundance of E. coli in HT. Therefore, the current study is in agreement with the hypothesis that HT patients have intestinal microbial dysbiosis. The taxa statistics at species-level along with each gut microbial community were modified in HT. Thus, the current study may offer the new insights into the treatment of HT patients, disease pathway, and mechanism

Efficacy and Safety of a Single Dose of Casirivimab and Imdevimab for the Prevention of COVID-19 Over an 8-Month Period: A Randomised, Double-Blind, Placebo-Controlled Trial

BACKGROUND: There is an unmet need for COVID-19 prevention in patient populations who have not mounted or are not expected to mount an adequate immune response to complete COVID-19 vaccination. We previously reported that a single subcutaneous 1200 mg dose of the monoclonal antibody combination casirivimab and imdevimab (CAS + IMD) prevented symptomatic SARS-CoV-2 infections by 81·4% in generally healthy household contacts of SARS-CoV-2-infected individuals over a 1-month efficacy assessment period. Here we present additional results, including the 7-month follow-up period (months 2-8), providing additional insights about the potential for efficacy in pre-exposure prophylaxis settings. METHODS: This was a randomised, double-blind, placebo-controlled trial done in the USA, Romania, and Moldova in 2020-2021, before the emergence of omicron (B.1.1.529) and omicron-lineage variants. Uninfected and unvaccinated household contacts of infected individuals, judged by the investigator to be in good health, were randomly assigned (1:1) to receive 1200 mg CAS + IMD or placebo by subcutaneous injection according to a central randomisation scheme provided by an interactive web response system; randomisation was stratified per site by the test results of a local diagnostic assay for SARS-CoV-2 and age group at baseline. COVID-19 vaccines were prohibited before randomisation, but participants were allowed to receive COVID-19 vaccination during the follow-up period. Participants who developed COVID-19 symptoms during the follow-up period underwent RT-PCR testing. Prespecified endpoints included the proportion of previously uninfected and baseline-seronegative participants (seronegative-modified full analysis set) who had RT-PCR-confirmed COVID-19 in the follow-up period (post-hoc for the timepoints of months 2-5 and 6-8 only) and underwent seroconversion (ie, became seropositive, considered a proxy for any SARS-CoV-2 infections [symptomatic and asymptomatic]; prespecified up to day 57, post-hoc for all timepoints thereafter). We also assessed the incidence of treatment-emergent adverse events. This study is registered with ClinicalTrials.gov, NCT04452318. FINDINGS: From July 13, 2020, to Oct 4, 2021, 2317 participants who were RT-PCR-negative for SARS-CoV-2 were randomly assigned, of whom 1683 (841 assigned to CAS + IMD and 842 assigned to placebo) were seronegative at baseline. During the entirety of the 8-month study, CAS + IMD reduced the risk of COVID-19 by 81·2% (nominal p INTERPRETATION: CAS + IMD is not authorised in any US region as of Jan 24, 2022, because data show that CAS + IMD is not active against omicron-lineage variants. In this study, done before the emergence of omicron-lineage variants, a single subcutaneous 1200 mg dose of CAS + IMD protected against COVID-19 for up to 5 months of community exposure to susceptible strains of SARS-CoV-2 in the pre-exposure prophylaxis setting, in addition to the post-exposure prophylaxis setting that was previously shown. FUNDING: Regeneron Pharmaceuticals, F Hoffmann-La Roche, US National Institute of Allergy and Infectious Diseases, US National Institutes of Health

Garetosmab in Fibrodysplasia Ossificans Progressiva: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing

Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial

Importance: Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage. Objective: To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported. Interventions: Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156). Main Outcomes and Measures: The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10copies/mL). Results: Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P =.04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P =.03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P =.001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19. Conclusions and Relevance: Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04452318

Hierarchical group testing for multiple infections

Group testing, where individuals are tested initially in pools, is widely used to screen a large number of individuals for rare diseases. Triggered by the recent development of assays that detect multiple infections at once, screening programs now involve testing individuals in pools for multiple infections simultaneously. Tebbs, McMahan, and Bilder (2013, Biometrics) recently evaluated the performance of a two-stage hierarchical algorithm used to screen for chlamydia and gonorrhea as part of the Infertility Prevention Project in the United States. In this article, we generalize this work to accommodate a larger number of stages. To derive the operating characteristics of higher-stage hierarchical algorithms with more than one infection, we view the pool decoding process as a time-inhomogeneous, finite-state Markov chain. Taking this conceptualization enables us to derive closed-form expressions for the expected number of tests and classification accuracy rates in terms of transition probability matrices. When applied to chlamydia and gonorrhea testing data from four states (Region X of the United States Department of Health and Human Services), higher-stage hierarchical algorithms provide, on average, an estimated 11 percent reduction in the number of tests when compared to two-stage algorithms. For applications with rarer infections, we show theoretically that this percentage reduction can be much larger

Topics in Group Testing with Multiple Infections

Group testing, dating back to the early 1940s, was first proposed to screen for syphilis among US inductees during World War II (Dorfman, 1943). Since then, the benefits of reducing testing costs by employing group testing have been demonstrated in many areas, such as drug discovery, genetics, and infectious disease testing. Traditionally, statistical research in group testing has largely been motivated by applications involving a single infection. With the recent development of multiplex assays that can diagnose multiple infections simultaneously, generalizing the existing group testing literature to incorporate multiple infections is a natural and necessary next step. This dissertation consists of three research projects that extend group testing to multiple infections. In Chapter 2 and Chapter 3, we propose two different testing algorithms to accommodate the use of multiplex assays. Compared to the two-stage hierarchical group testing algorithms currently employed by the Infertility Prevention Project (IPP) in Iowa, our algorithms are proven to confer significant cost savings. In Chapter 4, we propose a semi-parametric regression framework to estimate individual-level marginal probability of infection from multiple infection group testing data. The performance of our testing algorithms and estimation techniques is evaluated through numerical study, simulation, and application to chlamydia and gonorrhea data collected by five states as part of the IPP

Small signal stability constrained optimal power flow model based on trajectory optimization

The essence of traditional power system’s small signal stability analysis model using the eigenvalue analysis method is to analyze the time-invariant system obtained after the approximate linearization of the system, because it only considers the equilibrium state and therefore cannot consider the power system nonlinearity. In contrast, time-domain simulation can fully consider the system nonlinearity from the whole small signal dynamic period, because it considers not only the equilibrium state but also the state after the equilibrium point. On the basis of the time-domain simulation idea, this paper proposes an SSSC-OPF (small signal stability constrained-optimal power flow) based on optimizing the rotor angle trajectory. The objective function and the SSS constraint (small signal stability constraint) of the model are extracted from rotor angle curves of each generator, and the system stability is ensured by both in concert. Compared with the general SSSC-OPF model using the SSS constraint based on the eigenvalues, the proposed model can consider nonlinearity while avoiding the errors caused by the approximate linearization in the general SSSC-OPF model, and has a higher degree of generalizability. Finally, this paper performs the simulations in three test systems, the IEEE 9-bus test system, the IEEE 39-bus test system, and the IEEE 118-bus test system, and verifies the proposed model’s effectiveness by comparing the simulation results

Ground Temperature Monitoring and Simulation of Temperature Field Changes in Block-Stone Material Replacement Foundation for the Shiwei–Labudalin Highway

The current thermal balance of permafrost in northeastern China has been upset by human engineering construction disturbances and global warming. This has resulted in a rise in ground temperature and a fall in the permafrost table, which has a major impact on the stability, longevity, and operational safety of highway subgrades. To solve the issues above, the ground temperature monitoring data at K60+230 of the Shiwei–Labudalin highway were analyzed, and the numerical simulation of the temperature field change over 15 years was carried out for the ordinary subgrade as well as for sections of block-stone material subgrade with 1 m of straight-filled and different thicknesses of replacement fill (1 m, 2 m, 3 m, 4 m) by applying Comsol Multiphysis software. The results show that the temperature field of the subgrade exhibits significant asymmetry. There are variations in the rate of decline at different sites during the course of the 15 years when compared to where the permafrost table was located at the start of the study. Still, the rate of decline of the permafrost table is decreasing yearly. The straight-filled 1 m block-stone subgrade has a permafrost table 0.77 m higher in the bottom portion of its top surface than the ordinary subgrade. The replacement 1 m, 2 m, 3 m, and 4 m block-stone subgrade has a permafrost table in the lower portion of the top surface that is 1.05 m, 2.12 m, 3.32 m, and 4.75 m higher than the ordinary subgrade. The replacement block-stone subgrades, as opposed to ordinary subgrades, can strengthen the foundation, raise the permafrost table, and effectively reduce the impact of the upper boundary temperature on the lower permafrost. They can also increase the stability of permafrost subgrades. Of them, the block-stone filling with a thickness of 4 m and a particle size of 6–8 cm had the best impact

Monitoring of the Icing Process and Simulation of Its Formation Mechanism in the Cut Slope of Beihei Highway

Icing in cut slopes is a serious risk to transportation safety in cold regions. Research on the occurrence process and mechanism of icing is a prerequisite for proposing effective management measures. We took the cut slopes of the K162 section of the Beihei Highway as the research object. We used a combination of field investigation, geological exploration, monitoring, and simulation to study and analyze the power source, occurrence process, and triggering mechanism of icing in cut slopes. The results show that the geologic type of this cut slope is a mudstone–sandstone interaction stratum. Abundant shallow groundwater is the source of water for icing. The excavation of cut slopes extends the effect of negative temperatures on groundwater flow during the winter period. The process of ice formation in cut slopes can be described as follows: As the environmental temperature drops, the surface soil begins to freeze, resulting in a gradual narrowing of the water channel; then, the groundwater flow is blocked, so that the internal pressure begins to rise. When the internal pressure of the pressurized groundwater exceeds the strength of the frozen soil, groundwater overflows from the sandstone layer to the surface, forming icing. The high pore water pressure inside the cut slope is the precursor for the occurrence of icing. The dynamic pressure of the pore water pressure is the main driving force for the formation of icing in cut slopes. The obstruction of the water channel due to ground freezing is the triggering condition for ice formation in cut slopes

Synthesis of Silver Nanoparticles-Modified Graphitic Carbon Nitride Nanosheets for Highly Efficient Photocatalytic Hydrogen Peroxide Evolution

As a promising metal-free photocatalyst, graphitic carbon nitride (g-C3N4) is still limited by insufficient visible light absorption and rapid recombination of photogenerated carriers, resulting in low photocatalytic activity. Here, we adjusted the microstructure of the pristine bulk-g-C3N4 (PCN) and further loaded silver (Ag) nanoparticles. Abundant Ag nanoparticles were grown on the thin-layer g-C3N4 nanosheets (CNNS), and the Ag nanoparticles decorated g-C3N4 nanosheets (Ag@CNNS) were successfully synthesized. The thin-layer nanosheet-like structure was not only beneficial for the loading of Ag nanoparticles but also for the adsorption and activation of reactants via exposing more active sites. Moreover, the surface plasmon resonance (SPR) effect induced by Ag nanoparticles enhanced the absorption of visible light by narrowing the band gap of the substrate. Meanwhile, the composite band structure effectively promoted the separation and transfer of carriers. Benefiting from these merits, the Ag@CNNS reached a superior hydrogen peroxide (H2O2) yield of 120.53 μmol/g/h under visible light irradiation in pure water (about 8.0 times higher than that of PCN), significantly surpassing most previous reports. The design method of manipulating the microstructure of the catalyst combined with the modification of metal nanoparticles provides a new idea for the rational development and application of efficient photocatalysts