Leveraging Multi-National Observational Study in Post-Marketing Safety Assessment: Challenges and Strategies.

The use of multi-national observational study in post-marketing safety assessment has been rising in recent years in parallel with the rapid development and adoption of electronic healthcare data (e.g., administrative claims, electronic health records) and novel statistical analysis methods to handle these data.

Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans.

A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions.

DEMINERS enables clinical metagenomics and comparative transcriptomic analysis by increasing throughput and accuracy of nanopore direct RNA sequencing.

Nanopore direct RNA sequencing (DRS) is a powerful tool for RNA biology but suffers from low basecalling accuracy, low throughput, and high input requirements. We present DEMINERS, a novel DRS toolkit combining an RNA multiplexing workflow, a Random Forest-based barcode classifier, and an optimized convolutional neural network basecaller with species-specific training. DEMINERS enables accurate demultiplexing of up to 24 samples, reducing RNA input and runtime.

A simple and highly sensitive flexible sensor with extended-gate field-effect transistor for epinephrine detection utilizing InZnSnO sensing films.

This study introduces a straightforward method for depositing InZnSnO films onto flexible polyimide substrates at room temperature, enabling their application in electrochemical pH sensing and the detection of epinephrine. A comprehensive analysis of these sensing films, spanning structural, morphological, compositional, and profiling characteristics, was conducted using diverse techniques, including X-ray diffraction, atomic force microscopy, X-ray photoelectron spectroscopy, and secondary ion mass spectroscopy. The investigation into the influence of oxygen flow rates on the performance of InZnSnO sensitive films revealed a significant correlation between their structural properties and sensing capabilities.

The Seasonal Patterns, Ecological Function and Assembly Processes of Bacterioplankton Communities in the Danjiangkou Reservoir, China.

As the water source for the Middle Route Project of the South-to-North Water Diversion Project (MR-SNWD) of China, the Danjiangkou Reservoir (DJR) is in the process of ecosystem reassembly, but the composition, function, and assembly mechanisms of bacterioplankton communities are not yet clear. In this study, the composition, distribution characteristics and influencing factors of bacterioplankton communities were analyzed by high-throughput sequencing (HTS); PICRUSt2 was used to predict community function; a molecular ecological network was used to analyze bacterioplankton interactions; and the assembly process of bacterioplankton communities was estimated with a neutral model. The results indicated that the communities, function and interaction of bacterioplankton in the DJR had significant annual and seasonal variations and that the seasonal differences were greater than that the annual differences.

Integrative Analysis of Randomized Clinical Trial and Observational Study Data to Inform Post-marketing Safety Decision-Making.

Safety evaluation is a continual and iterative process throughout the drug development life cycle and requires long time horizons and large amounts of data to fully understand the safety profile of a medical product. Although randomized clinical trials (RCT) provide high-quality data for an initial assessment of safety signals, the safety signals may not all have been known at the time of approval because safety data collected from RCT only involve a relatively small number of subjects during a relatively short follow-up period. The increased accumulation of post-marketing real-world data (RWD) presents an opportunity to utilize them for safety decision-making; these include identifying new safety signals, further characterization of safety concerns that are raised in pre-marketing RCT, and further generalization of RCT findings to the broader patient populations not previously studied in RCT.

[Shifts in Rhizosphere Bacterial Community Structure, Co-occurrence Network, and Function of Following Cadmium Exposure].

As a representative of second-generation bioenergy plants, has received increasing attention in the studies of heavy metal (HM)-contaminated soil remediation. Currently, few studies have examined the effects of using to remediate HM-contaminated soils on the composition and function of microbial communities. In this study, the cultivar was examined for its tolerance and enrichment abilities when grown in soils containing 100 mg ·kg of cadmium (Cd).

Estimation of causal effect in integrating randomized clinical trial and observational data - An example application to cardiovascular outcome trial.

Safety evaluation of drug development is a comprehensive process across the product lifecycle. While a randomized clinical trial (RCT) can provide high-quality data to assess the efficacy and safety of a new intervention, the pre-marketing trials are limited in statistical power to detect causal elevation of rare but potentially serious adverse events. On the other hand, real-world data (RWD) sources play a critical role in further understanding the safety profile of the new intervention.

Bayesian hierarchical model for safety signal detection in multiple clinical trials.

Clinical safety signal detection is of great importance in establishing the safety profile of new drugs and biologics during drug development. Bayesian hierarchical meta-analysis has proven to be a very effective method of identifying potential safety signals by considering the hierarchical structure of clinical safety data from multiple randomized clinical trials conducted under an Investigational New Drug (IND) application or Biological License Application (BLA). This type of model can integrate information across studies, for instance by grouping related adverse events using the MedDRA system-organ-class (SOC) and preferred terms (PT).

Clinical evidence for association of neoadjuvant chemotherapy or chemoradiotherapy with efficacy and safety in patients with resectable esophageal carcinoma (NewEC study).

Background: The efficacy and safety of neoadjuvant treatment over surgery alone and that of neoadjuvant chemoradiotherapy (NCRT) over neoadjuvant chemotherapy (NCT) in resectable esophageal carcinoma remains inconclusive. This study (NewEC) used global data to comprehensively evaluate these comparisons and to provide a preferable strategy for patient subsets.

Methods: This study included a meta-analysis of randomized controlled trials (RCTs) identified from inception to May 2019 from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.

[Bacterial Community Composition in Cadmium-Contaminated Soils in Xinxiang City and Its Ability to Reduce Cadmium Bioaccumulation in Pak Choi ( L.)].

There are many types of bacteria in heavy metal-contaminated soils, including plant growth-promoting bacteria and heavy metal-immobilizing bacteria, which may potentially be used for the bioremediation of contaminated soil. In this study, the Cd-contaminated soil around a battery factory in Xinxiang City was collected and its bacterial community composition was analyzed using high-throughput sequencing (HTS) and the plate lineation separation method. The traditional culture method showed that bacteria isolated from contaminated soil belonged to four phyla (Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes) and 30 genera including , and .

Meta-analysis of blinded and unblinded studies for ongoing aggregate safety monitoring and evaluation.

During the course of clinical development, ongoing aggregate safety monitoring and evaluation are needed to understand the evolving safety profile and to ensure effective risk-management strategies for medicinal products. CIOMS reports and global regulatory guidance (including from ICH, US FDA, and EMA) compel sponsors for assessment of safety based on aggregate data. To identify and characterize the risks of medicinal products at a program level in a more timely and informed manner, aggregate safety evaluations should combine all available information, including from ongoing blinded trials, completed unblinded trials, and other data sources.

Bayesian Meta-analysis of Safety Outcomes Using Blinded Clinical Trial Data.

Background: During the development of an investigational new drug, identifying potential safety risks is imperative. Early detection, as well as federal regulations, requires safety monitoring procedures during clinical trials while the data are still blinded.

Method: We introduce a Bayesian meta-analytic approach for detecting a potential elevated safety risk conferred by an investigational treatment, as compared to control, using blinded data from multiple trials.

Rhizosphere Bacterial Community Structure and Predicted Functional Analysis in the Water-Level Fluctuation Zone of the Danjiangkou Reservoir in China During the Dry Period.

The water-level fluctuation zone (WLFZ) is a transitional zone between terrestrial and aquatic ecosystems. Plant communities that are constructed artificially in the WLFZ can absorb and retain nutrients such as nitrogen (N) and phosphorus (P). However, the microbial community composition and function associated with this process have not been elucidated.

Miscanthus cultivation shapes rhizosphere microbial community structure and function as assessed by Illumina MiSeq sequencing combined with PICRUSt and FUNGUIld analyses.

Soil microbes play important roles in plant growth and in the biogeochemical cycling of earth's elements. However, the structure and functions of the microbial community associated with the growth of second-generation energy crops, such as Miscanthus, remain unclear. Thus, in this study, the composition and function of the bacterial and fungal communities associated with Miscanthus cultivation were analyzed by MiSeq sequencing combined with PICRUSt and FUNGUIld analyses.

Nitrogen loss by anaerobic ammonium oxidation in a mangrove wetland of the Zhangjiang Estuary, China.

Anaerobic ammonium oxidation (anammox), a microbial process in which NH is oxidized to N gas, is considered a significant nitrogen cycle process, but its significance in mangrove wetland sediments, particularly its depth- and genus-specific distribution and activity have remained uncertain. Here we report the vertical distribution, abundance, activity and role of anammox bacteria in mangrove sediments of Zhangjiang Estuary, China. We used stable isotope-tracer techniques, 16S rRNA and anammox bacterial functional gene (Hydrazine synthase B: hzsB) clone libraries and quantitative polymerase chain reaction (qPCR) assays, along with an assessment of nutrient profiles of sediment core samples.

Bridging blinded and unblinded analysis for ongoing safety monitoring and evaluation.

In order to better characterize the safety profile of investigational new drugs (INDs) during clinical development, more interest and attention have been paid to ongoing safety monitoring and evaluation. The 2015 US FDA IND safety reporting draft guidance compels sponsors to periodically evaluate unblinded safety data. However, maintaining the trial blind is necessary to avoid jeopardizing the validity of study findings.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants.

Litorivita pollutaquae gen. nov., sp. nov., a marine bacterium in the family Rhodobacteraceae isolated from surface seawater of Xiamen Port, China.

A Gram-stain-negative Rhodobacterales strain, designated as FSX-11, was isolated from surface seawater of Xiamen port in China. Strain FSX-11 showed less than 96.5 % 16S rRNA gene sequence similarity to the type strains of species with validly published names.

Different Height Forms of Spartina alterniflora Might Select Their Own Rhizospheric Bacterial Communities in Southern Coast of China.

In the southernmost part of coast of China, two height forms of Spartina alterniflora, tall and short, have invaded Leizhou Peninsula within the last decade. However, the effect of different height forms of Spartina alterniflora on plant-microbe interaction has not been clarified. Here, the community structures of rhizosphere bacteria and the abundance of N- and S-cycling functional genes associated with selected S.

Bayesian regression model for recurrent event data with event-varying covariate effects and event effect.

In the course of hypertension, cardiovascular disease events (e.g., stroke, heart failure) occur frequently and recurrently.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.